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Review

Tumor Microenvironment: An Emerging Landscape for Lung Cancer Therapy

1
Graduate School of Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Chuo-ku, Hamamatsu 431-3192, Shizuoka, Japan
2
Department of Pharmacy, Islamic University, Kushtia 7003, Bangladesh
3
Department of Pharmacy, Khwaja Yunus Ali University, Sirajganj 6751, Bangladesh
4
Department of Life Technologies, Division of Biotechnology, University of Turk, FI-20014 Turku, Finland
5
ELSI, Institute of Science Tokyo, Tokyo 152-8550, Tokyo, Japan
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Future Pharmacol. 2025, 5(3), 34; https://doi.org/10.3390/futurepharmacol5030034
Submission received: 11 May 2025 / Revised: 20 June 2025 / Accepted: 23 June 2025 / Published: 30 June 2025

Abstract

The tumor microenvironment (TME) is crucial for the onset, development, and resistance to treatment of lung cancer. The tumor microenvironment consisting of a complex array of immune cells, fibroblasts, endothelial cells, extracellular matrix elements, and signaling molecules, facilitates tumor growth and spread while inhibiting the body’s antitumor immune response. In lung cancer, tumor-associated macrophages, cancer-associated fibroblasts, mast cells, and dendritic cells interact through cytokines, chemokines, growth factors, and matrix metalloproteinases to create an immunosuppressive and proangiogenic milieu. Hypoxic conditions within the TME further enhance cancer cell adaptability through hypoxia-inducible factors (HIFs), promoting epithelial–mesenchymal transition, immune evasion, and metastasis. Moreover, miRNAs have emerged as key regulators of gene expression within the TME, offering novel insights into tumor behavior and potential therapeutic targets. Targeting dynamic interactions within the TME, particularly through the modulation of immune responses, angiogenesis, and stromal remodeling, offers promising avenues for precision pharmacological approaches. This review covers the current understanding of the lung TME, highlighting its impact on cancer pathophysiology and treatment strategies. Understanding and therapeutically reprogramming the TME may pave the way for personalized and more effective interventions for lung cancer treatment.

1. Introduction

The cellular environment in which a tumor is situated is referred to as the tumor microenvironment (TME) [1]. The TME comprises a diverse array of cell types, including stromal, mesenchymal, and endothelial cells, as well as cancer-associated fibroblasts and cancer cells, each exhibiting unique phenotypic and genetic characteristics [2]. Within the lung tumor microenvironment, the principal components include cellular elements such as inflammatory cells, tumor cells, fibroblasts, non-vascular and vascular smooth muscle cells, and pericytic cells. Additionally, it encompasses soluble elements, including proteases, cytokines, and hormones [1]. Alterations in oncogenes that influence tumor growth and invasion of adjacent tissues are associated with the presence of anti-inflammatory infiltrates and can vary in size and shape among various tumor types and tumor development phases. Within tumors, the characteristics of complex inflammatory cells have been identified as being involved in both innate and adaptive immune responses to infiltrating lung cancer. Understanding the roles of these factors in tumor progression is essential for developing innovative anticancer therapies. Insights gained from this understanding will advance personalized medicine and facilitate the provision of targeted treatments aimed at reprogramming the tumor microenvironment to manage the disease effectively [3]. Lung cancer continues to pose a substantial global health challenge, with the highest incidence and mortality rates. Lung cancer is primarily divided into small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC), with NSCLC comprising 85% of all cases. This category includes adenocarcinoma, squamous cell carcinoma, and large cell carcinoma [4,5]. These subtypes differ in terms of therapeutic strategies and prognostic outcomes. NSCLC is typically managed with targeted therapies and has a 5-year overall survival rate of 23%. Conversely, SCLC is predominantly treated with platinum-based chemotherapy, with a median survival duration of less than one year [6]. In instances of advanced non-small cell lung cancer (NSCLC) where patients do not have identifiable driver gene mutations, immune checkpoint blockade (ICB) immunotherapy is the main treatment strategy [3]. Chemokines have emerged as pivotal elements in cancer immunotherapy, aiding communication between immune cells in the tumor microenvironment and encouraging their movement towards cancer cells [6]. Consistent with their ability to react to local environmental cues, pro-inflammatory interleukins and chemokines are present at high levels in the microenvironment of epithelial tumors [7,8]. The tumor microenvironment comprises T and B lymphocytes, which are components of adaptive immune responses. The phenotypes of these T- and B-cell subsets exhibit regulatory characteristics that attenuate the immunological response against the tumor and induce a chronic inflammatory state within the tumor microenvironment [9]. Several stimuli-responsive materials that degrade in the pathological tumor microenvironment (TME) have been produced and investigated for drug delivery applications using nanotechnological methods [10]. In the context of lung cancer and its complex tumor microenvironment (TME), where conventional treatments frequently encounter challenges such as drug resistance and immune evasion, traditional plant-based medicines are gaining popularity. Artocarpus chaplasha, a traditional medicinal herb, has demonstrated promising antioxidant and cytotoxic activities [11]. Despite substantial research, the role of the tumor microenvironment (TME) in immunotherapy resistance remains unexplained. Variable responses in NSCLC can be attributed to factors such as low MHC-I expression, inadequate neoantigen release, and restricted CD8+ T-cell infiltration. Understanding these mechanisms is crucial for overcoming resistance [12]. In recent years, a growing number of studies have highlighted the tumor microenvironment (TME), with Riera-Domingo et al. offering a complete overview of its metabolic features and hypoxia, as well as their impact on immune function and response to immunotherapies [13]. Understanding the complex interactions between tumor cells and TME components, such as immune and stromal cells, may lead to novel strategies for better lung cancer management and therapy [14]. Therefore, understanding the cellular and molecular interplay in the tumor microenvironment is crucial for developing effective therapeutic strategies. In this review, we focus on the cellular and molecular interplay in the lung tumor microenvironment and discuss several cellular and molecular components that can be targeted while developing therapeutics for personalized and more effective interventions in lung cancer treatment.

2. Tumor-Infiltrating Immune Cells

Tumor-infiltrating immune cells are surrounded by infiltrating inflammatory cells, especially macrophages and lymphocytes [15]. Evidence suggests that cancer malignancy is caused by both tumor-intrinsic characteristics and TME factors, particularly immune cell invasion. Lung cancer avoids immunosurveillance through low antigenicity, decreased MHC I/II/non-classical expression, a lack of co-stimulatory signals, and dysregulated immune cell infiltration [16]. The development of tumor-specific adaptive immune responses is particularly driven by tumor antigens [17]. The main components of tumor-specific cellular adaptive immunity are two types of T lymphocytes (CD4+ and CD8+ cells). CD8+ T lymphocytes target tumor cells by presenting tumor-associated antigen peptides in conjunction with the major histocompatibility complex class I (MHC I) on their surface and by secreting interferon-g (Table 1). Mechanisms of interferon-g-dependent tumor cell cytostasis and killing include cell cycle prohibition, angiostasis, apoptosis, and induction of antitumorigenic activity of macrophages [18].

2.1. Tumor-Infiltrating Lymphocytes (TIL)

Tumor-infiltrating lymphocyte (TIL) density, distribution, and phenotypic characteristics are important indicators of responsiveness to immune checkpoint inhibitors in lung cancer. TIL subsets (CD4+, CD8+, and CD19/20+) have both effector (antitumor) and suppressive (protumor) roles, which are influenced by the tumor environment. This balance ultimately determines the disease progression and immunological status.

Cytotoxic CD8+ T Lymphocytes

Higher CD8+ T densities are associated with improved overall survival rates in patients with lung cancer. CD8+ T cells are vital in the immunology of lung cancer, and higher levels within tumors are associated with better survival outcomes [24]. However, cancers avoid these cytotoxic cells via the following mechanisms:
  • MHC-I downregulation inhibits antigen presentation [25];
  • Regulatory T cells (Tregs) and myeloid cells secrete immunosuppressive cytokines, including TGFβ, IL-10, and IL-4 (Figure 1) [25];
  • Metabolic competition through IDO-mediated tryptophan/arginine depletion and excessive glycolysis starves T cells of glucose [26];
  • Upregulated immunological checkpoints (PD-1, CTLA-4, TIM-3, and LAG-3) cause T-cell “burnout” despite activation signals (Figure 1) [27,28].
Exhausted CD8+ TILs expressing multiple checkpoints resist ICI therapy. However, tumors rich in PD-1+CD8+ cells (“hot” TMEs) frequently respond better to PD-1 blocking [29]. Responders exhibited enhanced gene expression profiles with memory/effector signatures, whereas non-responders exhibited dysfunction-related genes (Table 1).
Figure 1. Various elements within the tumor microenvironment influence the regulation of immune responses in NSCLC. The figure is reprinted from Wang, Fen, et al., 2022 with free reuse permission [30].
Figure 1. Various elements within the tumor microenvironment influence the regulation of immune responses in NSCLC. The figure is reprinted from Wang, Fen, et al., 2022 with free reuse permission [30].
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3. Tumor Expressing Cytokines

Cytokines are proteins that may be either membrane-bound or secreted by innate and adaptive immune cells and which function as crucial regulators of immune homeostasis in response to tumor antigens and pathogens. Their effects depend on the local concentration, receptor availability, and integration of signaling pathways. The critical importance of cytokines in tumor immunity is highlighted by the increased incidence of tumors in animals lacking type I or II interferon receptors or associated signaling molecules [31]. Cytokines communicate through several shared receptor families, with type I, II, and III receptors being particularly significant in therapeutic applications (Table 2). Type I cytokines, such as IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21, initiate intracellular pathways via Janus kinases 1 and 3 and signal transducers of activated T cells [32].
The Oncostatin receptor and the leukemia inhibitory factor receptor (LIFR) facilitate signal transduction in heterodimeric complexes with glycoprotein 130 (gp130). Type II cytokine receptors, which include those for IFN-γ, IFN-α/β, IL-10, IL-20, IL-22, and IL-28, are composed of distinct signaling and ligand-binding chains [34]. IFN-1, IFN-2, and IFN-3, members of the recently identified type III family, activate the IL-10 receptor 2 and IL-28 receptor subunit complex [35]. Although there are currently no proven therapeutic applications for type III IFNs, this subgroup may prove crucial in the future. Malignant cell growth, survival, and death are caused by the JAK-STAT pathways, which are triggered by various combinations of JAK kinases and their substrates [36].

4. Lung Tumor Microenvironment

Lung cancer is characterized by the uncontrolled proliferation of cells within the lungs, predominantly involving epithelial cells, commonly referred to as carcinomas. Metastasis accounts for over 70% of mortality in Europe and the United States, while lung cancer remains the predominant cause of cancer-related fatalities. Most patients with end-stage lung cancer die within 18 months of diagnosis [37]. The lung tumor microenvironment is characterized by vascularization and oxygenation. Cigarette smoke induces an inflammatory response within the infiltrating inflammatory cells of the lungs, and the altered secretion of cytokines predisposes individuals to lung cancer [38]. The development of lung cancer and tissue preferences for metastasis results from the interaction between tumor cells and stroma and reflects the migration of cancer cells to release chemo-attractants instead of propagated cancer cells that may have the power to last in specific tissue microenvironments. Several stages are involved in the metastasis of epithelial cancers [39], including local tumor invasion through the cellular membrane and stroma [40], intravasation into the lymphatic system [41], survival of tumor cells within the circulation [42], attachment to the detached tumor site [43], acceleration of the development of circulating tumor cell microemboli [44], extravasation into the detached tissue microenvironment, which is facilitated by tumor-cell secreted factors [45], initial survival of tumor cells42434445 in the detached tumor stromal environment, responsible for the formation of a “pre-metastatic niche” [46,47], modification of the growth of cancer-cell intrinsic events at distant sites, and the development of macro metastases [29,48]. These steps act as barriers to dissemination, making the overall metastatic process inefficient. A substantial latency period between the primary diagnosis and subsequent formation of distant metastases is a general observation in epithelial carcinomas. It has been proposed that cells that depart from the primary tumor are sufficiently well adapted to survive at distinct metastatic sites so that the latency period of the lung does not occur [49]. This may also be considered a relatively late stage of almost all types of lung cancer diagnosis.

5. Cells of the Stroma

5.1. Fibroblast Cells

Fibroblasts were initially characterized in the late 19th century based on their anatomical location and microscopic morphology [50]. Fibroblasts are elongated cells with extensive cell processes that exhibit a fusiform or spindle-like shape. Fibroblasts play crucial roles in extracellular matrix (ECM) deposition, regulation of epithelial differentiation, and regulation of inflammation [51,52]. Fibroblasts synthesize many components of the fibrillar extracellular matrix (ECM), including type I, III, and V collagen and fibronectin [53]. These cells have a well-recognized role in the carcinogenic process. Stromal fibroblasts dominate tumor biology; however, the exact mechanisms involved remain unclear. Fibroblasts in mammals are highly disparate, and different sites reflect the substantial topographic diversity of these cells [54]. Cancer-associated fibroblasts (CAFs) are a distinct type of stromal cell characterized by myofibroblast features, α-smooth muscle actin (α-SMA) expression, and secretion of collagen and other extracellular matrix (ECM) protein. CAFs are now recognized for their role in epithelial tumor progression, growth, and metastasis by secreting substances that promote angiogenesis, cancer cell proliferation and invasion, macrophage recruitment, and T-cell-mediated immune suppression [55,56]. CAF lineages, characterized by their distinct functional roles, regulate the activities of immune, tumor, and endothelial cells. In lung cancer, the presence of PDGFR-α/β+ CAFs is associated with improved prognosis, whereas the secretion of ECM proteins by myofibroblastic CAFs is correlated with poorer outcomes. Given that factors derived from CAFs facilitate tumor growth, invasion, angiogenesis, and immune evasion, targeting CAFs is a promising strategy for cancer prevention and treatment [57]. Immunotherapy is typically ineffective in some patients with NSCLC owing to the lack of CD8+ T-cell penetration into tumors (Figure 2). CAF-rich tumors contribute to this by forming physical barriers and promoting an immunologically cool milieu. Interestingly, CAFs not only suppress the activity of CD8+ and CD4+ T cells but also promote the differentiation of regulatory T cells (Tregs) and recruit myeloid-derived suppressor cells (MDSCs), all of which collectively contribute to tumor progression and resistance to treatment. Cancer-associated fibroblasts (CAFs) exhibit resistance to chemoradiotherapy, which is attributed to their enhanced antioxidant defenses and DNA repair mechanisms, thereby facilitating tumor cell survival (Figure 2). In three-dimensional patient-derived lung cancer models, CAFs have been shown to promote resistance to various standard therapies. They achieve this by upregulating multidrug resistance proteins, such as ABCB1, which diminishes the efficacy of chemotherapeutic agents, including cisplatin, etoposide, and vinorelbine. Inhibition of CAFs through plasminogen activator inhibitor-1 (PAI-1) has been found to restore sensitivity to cisplatin. Furthermore, CAFs support cancer stem cells, contributing to treatment resistance. Molecular-targeted therapies, such as EGFR-TKIs and MET inhibitors, offer therapeutic benefits to specific subsets of NSCLC patients; however, cancer-associated fibroblasts (CAFs) can diminish their efficacy. CAFs engage in paracrine interactions that activate pro-inflammatory cytokine pathways, notably the OSM/STAT3 signaling pathway, thereby reducing drug sensitivity. Inhibition of STAT3 has been shown to restore the response to EGFR-TKI therapy. Furthermore, CAF-derived IGF-1 and HGF promote epithelial–mesenchymal transition (EMT) through the upregulation of ANXA2, contributing to therapeutic resistance. Targeting the HGF/IGF-1/ANXA2/EMT axis enhances TKI sensitivity. Additionally, CAFs induce metabolic reprogramming in NSCLC cells towards oxidative phosphorylation, while cancer cells promote glycolysis in CAFs, resulting in lactate production that fuels tumor growth. Prolonged TKI treatment increases lactate production, which stimulates HGF secretion from CAFs via the NF-κB pathway, thereby sustaining MET-driven resistance. Disruption of lactate signaling has been shown to reverse adaptive resistance [58]. Thus, targeting CAFs has the potential to improve immunotherapy responses in solid malignancies [59].

5.2. Immune Cells

Tumor cells induce angiogenesis and increase endothelial cell proliferation, thereby supporting tumor growth. Immune cells exhibit a paradoxical function in tumor progression; they initially fight tumor cells by producing cytokines, but eventually, tumors co-opt them to aid their growth and metastasis. Infiltrating immune cells are essential components of the tumor microenvironment, which tumor cells can use to cause immunological dysfunction and produce pro-inflammatory cytokines. Exosomal miRNAs facilitate intercellular communication, contributing to these activities [61]. Immune cells function as inhibitors of cancer spread, a notion first introduced by Ehrlich in 1909. Since then, extensive research has aimed to challenge, reassess, and confirm this theory. Over the past century, both in vivo and in vitro studies have demonstrated that various cancers, including breast, lung, and colorectal cancers, exhibit higher densities of infiltrating immune cells than normal tissues, highlighting a significant interaction between the immune system and tumor microenvironment [62].

5.2.1. T Cells

T cells are pivotal in adaptive immune responses; however, the tumor microenvironment (TME) can hinder antitumor activity through mechanisms such as immunomodulation and impaired antigen presentation. In various mouse cancer models, the depletion of regulatory T cells (Tregs) enhances antitumor T-cell responses and curbs tumor growth, underscoring the suppressive role of Tregs (Figure 3). Additionally, T-cell-derived amphiregulin (Areg), which can influence non-immune cells within the TME, promotes lung tumor development. Notably, this effect was not linked to changes in numbers of intratumoral T cells nor their capacity to produce pro-inflammatory cytokines, indicating that the absence of Areg, whether from all T cells or specifically from Tregs, does not significantly alter the immune landscape of the TME [63]. Regulatory T cells (Tregs) infiltrate tumors and suppress effector T-cell activity, which is essential for the recognition and elimination of cancer cells (Table 1). By promoting an immunosuppressive microenvironment, Tregs enable tumors to evade immune surveillance and accelerate their progression. Additionally, inflammatory factors play critical roles in disease development and regulation [64,65].

5.2.2. Macrophage

Macrophages account for the majority of inflammatory infiltration in malignancies [66], which is essential for inflammation and wound healing. Macrophages originate from monocytes in the bloodstream, which move into tissues and differentiate locally. Macrophages are essential components of the body’s primary immune response to infection and can exhibit antitumor activity under normal physiological conditions. When an immune response intended for healing is misdirected, TAM signaling facilitates tumor progression by enhancing vascularization, invasiveness, growth, cell survival, and immunosuppression [67]. Tumor-associated macrophages (TAMs) are macrophages that infiltrate the tumor microenvironment. These cells are often situated in proximity to cancer-associated fibroblasts (CAFs) and may interact with them. Notably, FAP-mediated cleavage of type I collagen by CAFs has the potential to activate macrophages [68]. Most malignancies exhibit a high prevalence of tumor-associated macrophages (TAMs) with the M2 phenotype, which is correlated with an unfavorable prognosis. These M2-like TAMs facilitate tumor survival, proliferation, and metastasis by promoting angiogenesis, epithelial-to-mesenchymal transition, and immunosuppression [69,70]. While the infiltration of M1 macrophages is uncommon in most cancer types, it has been documented in colorectal cancer, where it is associated with a more favorable prognosis, even in the presence of a predominance of M2 macrophages. The phenotype of tumor-associated macrophages (TAMs) is modulated by both the developmental stage of the tumor and its microenvironment (TME). Tumor progression is characterized by a dynamic interaction between intrinsic (genetic) and extrinsic (microenvironmental) factors, with one potentially initiating tumorigenesis and the other facilitating its progression [71,72].
Figure 3. The tumor microenvironment (TME) provides a dynamic and supportive environment in which various cell types constantly modify their phenotypes and functions. It is composed of a complex mix of mesenchymal stromal/stem cells (MSCs), tumor-associated fibroblasts (TAFs), and various immune cells, including macrophages, regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), natural killer (NK) cells, dendritic cells (DCs), monocytes, neutrophils, T lymphocytes, and B cells, as well as a diverse population of tumor cells. The figure is reprinted from Trivanović, Drenka, et al., 2016, with free reuse permission [73].
Figure 3. The tumor microenvironment (TME) provides a dynamic and supportive environment in which various cell types constantly modify their phenotypes and functions. It is composed of a complex mix of mesenchymal stromal/stem cells (MSCs), tumor-associated fibroblasts (TAFs), and various immune cells, including macrophages, regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), natural killer (NK) cells, dendritic cells (DCs), monocytes, neutrophils, T lymphocytes, and B cells, as well as a diverse population of tumor cells. The figure is reprinted from Trivanović, Drenka, et al., 2016, with free reuse permission [73].
Futurepharmacol 05 00034 g003

5.2.3. Mast Cells

Paul Ehrlich initially characterized mast cells (MCs) as adaptable, tissue-resident secretory cells. He observed an increase in MCs within chronically inflamed tissues and hypothesized that they supplied nutritional support to damaged cells [74]. Their distribution across vascularized tissues exposed to the external environment, including the lungs, facilitates interaction with environmental antigens, invading pathogens, or toxins [75]. Mast cells (MCs) are a type of innate immune cell located at the tumor periphery and in the tumor microenvironment (TME), frequently near blood vessels. MCs, which differ from bone marrow progenitors, circulate in the blood and are guided to certain organs by chemotactic signals. Several cytokines, including stem cell factor (SCF), CXCL12, IL-3, IL-4, IL-9, IL-10, IL-33, and TGF-β, influence survival and proliferation. While MCs have generally been examined in the context of allergic reactions, recent research has revealed that they can act as pro-inflammatory and angiogenic mediators in malignancies. When activated, MCs produce mediators that attract immune cells such as neutrophils, macrophages, eosinophils, and B and T cells, thereby contributing to antitumor immune responses [76]. Mast cells (MCs), which are involved in inducing inflammation and angiogenesis in the tumor microenvironment (TME), are intriguing targets for adjuvant cancer therapy. Strategies may include suppressing angiogenesis and tissue remodeling, restricting the production of tumor-promoting proteins, and reversing MC-driven immune suppression, while increasing their ability to produce cytotoxic cytokines, which boosts anticancer effectiveness [77].

5.2.4. Dendritic Cells

Dendritic cells (DCs) initiate, maintain, and direct antitumor immune responses. They detect DAMPs generated by dying tumor cells, which induces cytokine production and T-cell activation [78]. Dendritic cells (DCs) capture antigens and migrate to lymph nodes to present them to CD8+ T cells. They are primarily categorized into two types: conventional type 1 (cDC1s), which activate CD8+ T cells and enhance antitumor immunity, and conventional type 2 (cDC2s), which prime CD4+ T-cell responses (Figure 3). cDC2s are further divided into anti-inflammatory cDC2A (T-bet+) and pro-inflammatory cDC2B (T-bet) cells based on their transcriptional and chromatin profiles. A high infiltration of cDC1 is correlated with an increased presence of T cells and improved prognosis. Tumors may evade immune detection by limiting the access of cDC1 to the tumor microenvironment [79,80]. cDC1s use the C-type lectin receptor DNGR-1 to identify F-actin in necrotic cells, which activates CD8+ T lymphocytes by antigen absorption and cross-presentation. However, tumor-secreted gelsolin (sGSN) can disrupt this mechanism by preventing DNGR-1-dependent cross-presentation, thereby reducing the immune response [81,82]. Plasmacytoid dendritic cells (pDCs), which are recognized for their substantial production of IFN-α, resemble plasma cells. In breast and ovarian cancers, pDCs are dysfunctional, secreting reduced levels of type I IFN and facilitating the development of regulatory T cells (Tregs), thereby contributing to tumor progression. The mechanisms underlying dendritic cell differentiation within the tumor microenvironment remain a subject of ongoing investigation and have significant implications for the development of future immunotherapies [83].

5.2.5. Vascular Cell

VEGF-C expression has been reported in NSCLC, with expression of carcinoma cells—unlike stromal cells—identified as a significant prognostic factor. In this study, VEGF-C/VEGFR-3 coexpression was observed in 39% of tumors, consistent with previous reports but with varying results. It was reported that VEGF-C and VEGFR-3 were expressed in 72% and 52% of cases, respectively, with a significant positive correlation [84]. Tumors construct an intricate vascular network to meet their metabolic and nutritional requirements. VEGF, mainly secreted by tumor cells, fibroblasts, and inflammatory stromal cells, initiates this development by activating the “angiogenic switch”. Nevertheless, the vessels formed under the influence of VEGF are abnormal, irregularly shaped, poorly branched, tortuous, and frequently end blindly. Without a normal vascular hierarchy, these vessels may form arteriovenous shunts and are characterized by leakiness and variable fenestration, leading to increased interstitial pressure and worsened hypoxia, further stimulating VEGF production [85,86]. Under the influence of VEGF, tumor vasculature develops through various mechanisms, including the initiation of vascular networks, the recruitment of vascular progenitor cells to form new vascular channels, or through “vascular mimicry”, which is a process whereby tumor cell-lined channels contribute to the tumor’s blood supply by offering an alternative vascular pathway that operates independently of traditional endothelial vessels [87].

6. Extracellular Molecules

6.1. Cytokines

Given the limitations of current lung cancer treatments, the development of immune-based alternatives is critical. TILs in the tumor microenvironment (TME), including lymphocytes and macrophages, release low-molecular-weight cytokines and chemokines (<30 kDa) that govern cellular activities such as metabolism, proliferation, tissue repair, and chemotaxis. These chemicals act on specific cell receptors to facilitate intercellular communication via autocrine, paracrine, and endocrine signaling pathways [88,89]. Cytokines and chemokines orchestrate immune responses and drive local and systemic inflammation, and they also have a substantial impact on tumor growth, metastasis, and therapeutic resistance in the tumor microenvironment (TME). Several cytokines, including IL-6, IL-10, IL-17, IL-27, IL-35, TNF-α, IFN-γ, and TGF-β, and chemokines, such as CCL-2, CCL-5, CCL-18, CCR4, CXCR4, CX3CL1, CXCL-1, CXCL-5, CXCL-8, and CXCL-13, have been extensively explored as therapeutic targets and biomarkers in lung cancer therapy techniques (Table 3) [90]. The interleukin-1 (IL-1) cytokine family, comprising IL-1β and IL-1α, plays a crucial role in modulating immunological responses by regulating inflammation and innate immunity. IL-1 promotes IFN-γ production in T and NK cells, thereby affecting the tumor microenvironment. Elevated IL-1β levels in lung cancer can lead to persistent inflammation, macrophage infiltration, and tissue remodeling, potentially favoring tumor growth and genetic alterations (e.g., such as TP53). High IL-1 levels in malignancies are associated with poor prognosis. Therapeutic methods targeting IL-1 signaling, such as IL-1 inhibitors and the IL-1 receptor antagonist anakinra, are being investigated to inhibit inflammation-driven tumor growth and modify antitumor immunity [66,91,92]. Furthermore, interleukin-2 (IL-2) is a cytokine synthesized by T cells that plays a crucial role in initiating immunological responses. In cancer therapy, IL-2 (as aldesleukin) increases T- and B-lymphocyte activity, which improves antitumor immunity. Clinical trials have shown that IL-2, either alone or in combination with chemotherapy, improves survival in patients with advanced malignancies, such as NSCLC. In China, IL-2 is licensed for the treatment of malignant pleural effusion (MPE), particularly in combination with cisplatin administered via thoracic injection, and it has demonstrated enhanced efficacy and safety [33]. IL-4 and IL-13, cytokines associated with type 2 innate lymphoid cells (ILC2), are crucial in mediating interactions between tumors and the immune system through the type II IL-4 receptor (IL-4Rα/IL-13Rα1). These cytokines facilitate the progression, growth, and immune evasion of various solid tumors, including lung cancer. By activating common signaling pathways, IL-4 and IL-13 promote carcinogenesis and affect the tumor microenvironment [93]. Lung tumor-derived prostaglandin E2 (PGE2) regulates immunological responses by increasing IL-10 synthesis from lymphocytes and macrophages while decreasing IL-12 production by macrophages. Through immunohistochemical examination of NSCLC tissues, researchers have identified cytoplasmic COX-2 expression within tumor cells, providing initial evidence of functional COX-2 in NSCLC. This finding implies that increased COX-2 and PGE2 levels may disrupt cytokine equilibrium and transform the immune microenvironment associated with lung cancer [94]. Clinical research has demonstrated that elevated prediagnostic plasma concentrations of IL-6 and IL-8 are correlated with an increased risk of lung cancer, particularly squamous cell and small-cell carcinoma, among current and former smokers. Although cytokine levels were associated with smoking behavior, adjusting for cotinine had no effect, implying that IL-6 and IL-8 may indicate inflammation-related cancer risk beyond tobacco exposure (Table 3) [95]. Higher levels of IL-1β and IL-6 were found in bronchoalveolar lavage (BAL) cell cultures and blood of lung carcinoma patients. TNF-α and IL-1β work together to promote tumor cell cytotoxicity by stimulating IL-1 production. IL-6 rise may come from intrinsic tumor cell production or stimulation-induced release, accompanied by enhanced secretion by CD4+ T cells that produce Th2 cytokines [96].

6.2. Growth Factors

Epidermal growth factor is a trans-membrane glycoprotein. Epidermal growth factor (EGF) promotes the growth of cultured benign and malignant cells. Recent studies have shown that the amount of EGF receptor in squamous cell carcinoma cells in tissue culture increased compared with normal epidermal cells [98]. Epidermal growth factor (EGFR) is a receptor tyrosine kinase that is highly expressed in cancer cells, including lung cancer cells. These transmembrane proteins are aerated by binding to peptide growth factors of the EGF family of proteins. Mechanisms that augment signaling by growth factors have been identified. For instance, the overexpression of receptors on the surfaces of tumor cells can enhance their sensitivity to low concentrations of growth factors derived from either the host or the tumor itself. Furthermore, there is a direct correlation between growth factors and proto-oncogenes [99]. Genetic changes, notably EGFR mutations, play an important role in the activation of growth factor signaling in lung cancer. These mutations increase both autocrine and inducible EGFR activation, promoting tumor development and metastasis [100,101]. A considerable subset of NSCLC adenocarcinomas, particularly non-mucinous bronchioloalveolar carcinoma (BAC), has high EGFR mutation rates, reaching up to 80% in some Japanese cohorts. These individuals frequently respond to EGFR tyrosine kinase inhibitors (TKIs), making EGFR an important therapeutic target for NSCLC. Lung adenocarcinomas exhibit a variety of histological features, including acinar, papillary, solid, lepidic, and micropapillary [102,103]. Extensive evidence indicates that EGFR is a key therapeutic target in lung cancer. Two major techniques have been developed: (1) tyrosine kinase inhibitors (TKIs) that disrupt EGFR signaling (e.g., erlotinib and gefitinib) and (2) monoclonal antibodies that neutralize EGFR or its ligands (e.g., cetuximab and bevacizumab). These inhibitors have been demonstrated to effectively reduce tumor development, induce apoptosis, and limit metastasis. Preclinical research, including in vitro and in vivo models, has demonstrated that combining cetuximab with chemotherapy or radiotherapy has a synergistic impact, greatly increasing lung cancer cell death [102]. Clinical trials with EGFR inactivators, particularly gefitinib, initially demonstrated promise, with 20% tumor response and 40% symptom alleviation in patients with NSCLC [104,105]. However, phase III trials demonstrated little improvement in survival, and gefitinib alone or in conjunction with chemotherapy did not enhance the results. In contrast, erlotinib displayed more therapeutic value, with significant survival advantages when administered in combination with chemotherapy, even in phase III double-blind trials, making it a more effective EGFR-targeted alternative for advanced NSCLC [106,107]. Many lines of evidence suggest that EGFR is relevant to patients with NSCLC and may serve as a potential therapeutic target. EGFR expression was observed by immunohistochemistry testing in 62% to 93% of resected primary tumors, and EGFT mRna was found in 100% of cases. EGFR overexpression is variably correlated with clinical outcomes [104].

6.3. Matrix Metalloproteinase

Growing evidence indicates that extracellular proteinases, notably matrix metalloproteinases (MMPs), play an important role in mediating microenvironmental alterations during tumor growth. These enzymes govern a wide range of physiological activities and signaling pathways, making them critical to the molecular interactions between tumor cells and the stroma [40]. Matrix metalloproteinases (MMPs) are a class of zinc-dependent endopeptidases discovered about 50 years ago. They are required for various physiological activities, including tissue remodeling, wound healing, and organ development, as they degrade extracellular matrix components and modulate cell activity [108,109]. Certain MMPs have tumor-suppressive roles, which explains the limited success of broad-spectrum MMP inhibitors (MPIs) in cancer therapy. For example, MMP-8 deficiency increases the risk of cancer, and macrophage-derived MMP-12 suppresses lung metastasis by modulating tumor vasculature. Additionally, MMPs can exert non-proteolytic effects via domains such as hemopexin, which are not targeted by typical MPIs, thereby reducing their therapeutic efficacy [40]. Matrix metalloproteinases (MMPs) eliminate extracellular matrix (ECM) components and play an important role in cancer invasion and metastasis. MMPs and their inhibitors (TIMPs) are both high in lung malignancies such as SCLC; however, the imbalance favoring MMP activity promotes tumor spreading. MMP2, for example, cleaves laminin 5, exposing a promigratory site that increases cell motility, which is present in tumors but not in normal tissue. Targeting MMP-driven ECM remodeling, such as MMP2-mediated laminin 5 cleavage, could lead to more precise and effective lung cancer therapy [110]. MMP-2 knockdown by adenoviruses inhibits tumor growth and lung nodule formation. MMP-7 inhibition via fibulin-3 hypermethylation or miR-134 reduces metastasis and invasion. MMP-12 inhibition, either pharmacologically (e.g., with oridonin) or by gene knockdown, reduces lung adenocarcinoma cell invasion, migration, and proliferation. These findings highlight the potential of targeting individual MMPs to develop more precise and effective lung cancer treatments [111].

7. Immune Regulation by Stroma

Initially showing tumor-suppressive characteristics, stromal cells change during malignancy, which eventually makes it easier for tumors to grow, invade, and spread. Notably, carcinoma-associated fibroblasts (CAFs) frequently appear along the invasive front. Until recently, cancer research has largely focused on malignant cells, leaving a gap between experimental results and therapeutic use. However, understanding the tumor microenvironment is now considered as important as understanding cancer genetics. Tumors are composed not only of cancerous cells but also of stromal elements, such as fibroblasts, immune cells, endothelial cells, and mesenchymal cells, which malignant cells may enlist to promote their growth and spread [112]. Angiogenesis is required for tumor development and survival and remains the most successful stromal target in cancer treatment. The process begins with MMP-induced basement membrane disintegration, endothelial cell sprouting, and pericyte regulation. CAFs produce ECM components and important growth factors, including TGF-β, VEGF, and FGF2 [113]. Immune system dysfunction is strongly associated with NSCLC, and immune checkpoint inhibitors are currently important second-line treatments following chemotherapy failure. Treatments targeting CTLA-4, PD-1, and PD-L1 have demonstrated efficacy in lung cancer. Pembrolizumab increased progression-free and overall survival in patients with NSCLC, but TG4010 with chemotherapy improved PFS in advanced cases [114]. The proliferation of fibroblasts and dense ECM deposition in the tumor stroma is known as desmoplastic reaction. Unlike alveolar collapse, desmoplasia features activated fibroblasts and abundant collagen. Initially thought to be a defense mechanism against tumor growth, it is now recognized as a contributor to tumor progression, including angiogenesis, invasion, and metastasis. Fibroblasts and tumor cells promote this progression by remodeling the ECM, releasing stored factors such as VEGF, and generating bioactive fragments through MMP activity [112]. Activated fibroblasts are known as carcinoma-associated fibroblasts (CAFs) or peritumoral fibroblasts in malignant tumors. CAFs have comparable beginnings and are extremely diverse, similar to their normal counterparts. Although the majority of myofibroblasts originate from local fibroblasts, they can also originate from pericytes, vascular smooth muscle cells, mesenchymal cells originating from the bone marrow, or epithelial or endothelial-to-mesenchymal transition [115,116,117]. Fromigue et al. found that NSCLC cells can reprogram normal pulmonary fibroblasts in co-culture, affecting the expression of genes associated with matrix disintegration, angiogenesis, invasion, and cell survival. Recent translational research on resected NSCLC tissues has indicated the prognostic functions of CAFs. Carbonic anhydrase IX expression in CAFs was a better predictor of adenocarcinomas than in cancer cells. In addition, an autocrine HGF/c-MET signaling loop in CAFs may increase tumor invasiveness. Podoplanin expression in CAFs, but not in tumor cells, was also associated with lower patient survival [112]. Immune cells, including monocytes/macrophages, neutrophils, and lymphocytes, penetrate the tumor stroma. Monocytes are attracted by chemotactic gradients and transform into tumor-associated macrophages (TAMs), which settle in hypoxic and necrotic areas, where they enhance the expression of hypoxia-induced transcription factors. TAMs release proangiogenic factors, such as VEGF, HGF, MMP2, and IL-8, which affect the endothelial cells. Neutrophils also aid in angiogenesis by emitting similar factors. Other immune cells, such as myeloid-derived suppressor cells (MDSCs), play a role in immune suppression and may become part of the vessel walls, although their function is less clearly defined and varies with tumor type [118,119].

8. Hypoxia and Tumor Microenvironment

Hypoxia is a common and significant characteristic of solid tumors. Hypoxic tissue is defined as having an oxygen tension of less than 10 mmHg, compared with 40–60 mmHg in most normal tissues [120]. Cancer-related inflammation contributes to tumor initiation and progression by enhancing genomic instability, cell proliferation, angiogenesis, apoptosis resistance, and metastasis. Hypoxia also contributes to tumor cells’ evasion of immune attack and avoidance of immunosurveillance. Hypoxia-inducible factors (HIFs), which are essential for hypoxic signaling, control genes implicated in tumor immune responses in low-oxygen environments [121]. The underlying mechanism behind these effects is often mediated by the induction of the hypoxia-inducible factor (HIF) family of transcription factors. This family consists of three members: HIF-1, HIF-2, and HIF-3, which regulate cellular processes such as glucose metabolism, angiogenesis, cell proliferation, and tissue remodeling in response to low oxygen concentrations. Under normal oxygen conditions, a group of prolyl-4-hydroxylases (PHDs) hydroxylate HIF-1α at two conserved residues, proline 402, and proline 564 [122,123,124]. One strategy is to ameliorate drug delivery, thereby enhancing drug accumulation in tumors. Several treatment techniques for hypoxia have been developed to address this issue. Hypoxia is crucial in the lung cancer tumor microenvironment, affecting cell survival and proliferation by modifying intracellular protein synthesis. In non-small cell lung cancer (NSCLC), hypoxia facilitates proliferation, metastasis, and resistance to apoptosis by inducing angiogenesis and metabolic reprogramming. Cancer-derived extracellular vesicles (EVs) aid survival in hypoxic conditions by enhancing intercellular communication and controlling angiogenesis, immunological evasion, cell migration, and invasion [125,126]. NSCLC cells adapt to hypoxia by switching to glycolytic metabolism, which, like the Warburg effect, favors glucose-to-lactate conversion even in the presence of oxygen. This hypoxic adaptation helps improve invasiveness and resistance to treatment. Furthermore, hypoxia inhibits DNA repair and alters the tumor morphology, thereby lowering the efficacy of radiation, chemotherapy, immunotherapy, and targeted therapies [127]. In NSCLC, hypoxia is a major contributor to treatment resistance, leading to the development of focused tactics to enhance results. These strategies include lowering oxygen consumption (e.g., metformin, atovaquone), boosting oxygen delivery (e.g., carbogen with nicotinamide, efaproxiral), and increasing hypoxic cell radiosensitivity (e.g., misonidazole, nimorazole). Other strategies include inhibitors of hypoxia-related pathways, such as aryl sulfonamides that target HIF-1α and hypoxia-activated prodrugs, such as tirapazamine, evofosfamide, and tarloxotinib bromide [128,129]. Dose-painting-by-numbers (DPBN) provides increased radiation to hypoxic subvolumes, enhancing tumor control by 10–15% while maintaining lung NTCP below 1%. It is robust to positional (<3 mm) and radiosensitivity variations [130]. Bevacizumab normalizes the tumor vasculature, improving perfusion and oxygen/drug delivery. At modest dosages, it boosts the perfused vascular fraction in hyperpermeable tumors from 0.2 to 0.45, thereby improving chemotherapeutic efficacy [131]. Combining perflubron with 60% respiratory oxygen eliminates tumor hypoxia, decreases adenosine signaling, enhances CD8+ T- and NK-cell infiltration, and reduces tumor burden by 40–60% in preclinical models. Hyperbaric oxygen therapy (HBOT) improves tumor oxygenation, reduces radiation-induced necrosis, and aids in postsurgical wound healing [132]. DESI-MSI reveals metabolic heterogeneity in hypoxic tumor regions, marked by elevated palmitoyl- and stearoyl-carnitines, which support β-oxidation. These lipid changes reflect local oxygen tension and contribute to remodeling of the microenvironment [133]. Another technique is to directly provide oxygen to the tumor using technologies such as the catalytic breakdown of endogenous hydrogen peroxide (H2O2) and light-triggered water splitting [134]. Several ongoing clinical trials are investigating hypoxia-targeted therapeutics using various medicines with distinct mechanisms. HIF inhibitors, including PX-478 and LW6, are an important class of therapeutic agents. Studies have revealed that HIF inhibitors, either alone or in conjunction with other therapies, exhibit promising antitumor properties [121]. Osimertinib, a third-generation EGFR-TKI for NSCLC, inhibits the interaction between UBL3 and α-synuclein in cells. This may affect the HIF-1α/TGF-α axis in EGFR T790M-mutant lung cancer, alone or in combination with bevacizumab. Triple therapy with osimertinib, bevacizumab, and cetuximab can achieve profound remission in EGFR-mutant tumors expressing HIF-1α/TGF-α [135,136].

9. Role of microRNAs in Regulating the Tumor Microenvironment

miRNAs are short, noncoding RNAs (18–25 nt) that control gene expression by binding to target mRNAs, primarily in the 3′-UTR, causing repression or destruction [137]. They are produced as lengthy primary transcripts (pri-miRNAs) and then processed in the nucleus by Drosha-DGCR8 into precursor miRNAs (pre-miRNAs) before being exported to the cytoplasm. Dicer further converts them into mature miRNAs, which are then placed into the RISC complex to control gene silencing [138,139]. miRNAs can target hundreds of mRNAs and have important functions in development, proliferation, apoptosis, and cancer. Although they are mostly active in the cytoplasm, they can also be found in the nucleus and nucleolus, and their roles are currently being investigated [140]. According to studies, a single miRNA can bind to over 200 target genes, altering processes such as transcription, receptor activation, and gene transport. This intricacy makes it difficult to determine the exact transcripts and pathways controlled by individual miRNAs [141]. MicroRNAs have been shown to be involved in various cellular processes, including proliferation, development, metabolism, differentiation, and apoptosis. Most importantly, pathological conditions involving cancer have been associated with the deregulation of miRNA expression and function [142,143]. Many miRNAs, including let-7, miR-15a, miR-16, miR-34a/b, miR-125, miR-155, miR-192, and miR-486, are downregulated in lung cancer compared with other miRNAs, including miR-21, miR-194, and miR-186, which are frequently overexpress. Experimental studies have revealed that restoring tumor-suppressive miRNAs, such as miR-101, miR-186, miR-200, and miR-129, inhibits lung cancer cell proliferation, tumor growth, and metastasis, indicating their potential as therapeutic targets (Table 4) [140,144,145]. For instance, miR-192 lowers cancer levels in vivo and prevents proliferation in A549, H460, and 95D cells. Likewise, miR-34a and miR-193b decrease the survival of A549 cells, whereas miR-34a also inhibits the growth of SCLC cells. In contrast, blocking oncogenic miRNAs, such as miR-150 and miR-223, slows the growth of lung cancer cells, highlighting the dual function of miRNAs as biomarkers and therapeutic targets [140,146,147]. Defective apoptosis is a major cause of tumor formation and progression. Caspases, enzymes that activate or deactivate cellular targets, are responsible for apoptosis. Caspase activation occurs via two major pathways: extrinsic (activated by death receptors such as TNF, Fas, and TRAIL) and intrinsic (mitochondrial) [148]. Recent research suggests that miRNAs that are frequently overexpressed in cancer, including miR-19a from the miR-17–92 cluster, can block apoptosis by targeting tumor necrosis factor alpha (TNF-α) and TRAIL. Targeting these miRNAs may provide novel techniques for restoring apoptosis in lung cancer; however, further research is required [149,150]. In NSCLC, multiple miRNAs regulate TRAIL-induced apoptosis. MiR-34a, miR-34c, and miR-212 were downregulated and increased TRAIL-mediated cell death when overexpressed. In contrast, miR-494a, miR-221, and miR-222 contribute to TRAIL resistance (Table 4) [151,152]. Blocking miR-221/222 improved TRAIL sensitivity by increasing p27 expression. miR-130a can also reduce TRAIL resistance by inhibiting miR-221/222 via c-Jun downregulation. These findings show that miRNAs can either increase or inhibit apoptosis in lung cancer, suggesting novel therapeutic targets [153,154]. Circulating miRNAs in human serum and plasma have persistent and distinct expression patterns, making them ideal non-invasive indicators. Their levels are associated with cancer progression, therapeutic efficacy and patient survival. As such, miRNA profiles have great potential as diagnostic and prognostic markers for lung cancer and other cancers [155,156]. Furthermore, miRNAs regulate chemotherapy resistance in NSCLC by maintaining DNA repair, autophagy, and drug transport pathways. For example, miR-149 suppresses ERCC1, restoring cisplatin (CP) sensitivity, whereas miR-488 enhances resistance via XPC. miR-23a, miR-138-5p, miR-124, and miR-142 improve CP sensitivity by suppressing autophagy, whereas miR-1269b enhances resistance via the PTEN/PI3K/AKT pathway. In addition, miR-98-5p restores resistance by targeting the drug transporter, CTR1 [157]. In NSCLC, lncRNA FGD5-AS1 sponges miR-454-3p, increasing ZEB1, PD-L1, and VEGFA levels, and encouraging angiogenesis and immune evasion [158]. The EGFR-P38 MAPK pathway activates PD-L1 via miR-675-5p, thereby increasing its mRNA stability. PTEN loss stimulates PI3K, which suppresses cytotoxic T-cell activity and reduces antitumor immunity [159,160]. Furthermore, miR-103a reduces PTEN levels in tumor-associated monocytes, boosting M2 macrophage polarization and activating AKT/STAT3 signaling, thereby promoting tumor immunosuppression. These pathways provide therapeutic targets for enhancing the immune response in NSCLC [157,161]. miRNAs influence immunological checkpoints such as CTLA-4 and PD-1/PD-L1, affecting lung cancer immune responses and immunotherapy results. For example, miR-146a is associated with increased CTLA-4 expression and may predict immune checkpoint inhibitor (ICI) treatment responses in advanced NSCLC. MiR-33a levels were negatively correlated with PD-L1 levels, with higher levels associated with a better prognosis and showing potential as a biomarker for PD-1 therapy. Let-7b inhibits PD-1/PD-L1 expression, which boosts CD8+ T-cell antitumor activity. These miRNAs show promise as targets and indicators of improved lung cancer immunotherapy. In addition, combining miRNA-based treatments with immunotherapy to modulate immunological checkpoints and increase T-cell sensitivity shows significant promise for improving antitumor effects in lung cancer [157]. The development of miRNA-based cancer therapeutics faces significant hurdles, including miRNA instability in circulation and low uptake of target cells. MiRNAs are quickly destroyed by RNases and are hydrophilic and negatively charged; therefore, effective delivery mechanisms are essential for improving their stability, bioavailability, and targeting precision [162]. Promising miRNA delivery techniques include lipid nanoparticles (LNPs), polymeric nanoparticles such as PLGA, and exosomes. LNPs preserve miRNAs from degradation, allowing controlled release, and can be tailored with targeting ligands to improve precision and limit off-target effects. Polymeric nanoparticles provide tumor-specific delivery by responding to stimuli such as pH and enzymes in the tumor microenvironment, resulting in localized miRNA release. Exosomes provide natural, biocompatible delivery with low immunogenicity and can be modified for larger payloads and tailored distribution. However, hurdles remain. LNPs may have off-target effects, polymer-based systems require precise release control, and exosome treatments face barriers to large-scale production and clinical implementation. Overcoming these challenges is critical for the success of miRNA therapies [162,163,164].

10. Role of Cells in the Tumor Microenvironment

The tumor microenvironment (TME) plays a critical role in supporting cancer stem cells (CSCs) in lung cancer, influencing their survival, self-renewal, and resistance to therapy. Various cell populations within the TME, including cancer-associated fibroblasts (CAFs), tumor-infiltrating lymphocytes (TILs), and regulatory T cells (Tregs), contribute to this support through complex interactions and signaling pathways in the TME (Table 5).

11. The Antitumor Properties of Natural Extracts and Phytochemicals Against Lung Cancer

Copper nanoparticles (CuNPs) have demonstrated significant anticancer potential, particularly in lung cancer. Studies have shown that CuNPs exert a strong inhibitory effect on the proliferation of lung cancer cell lines. Moreover, the Fe3O4/chitosan/Cu (II) nanocomposite markedly reduced the viability of malignant lung cells in a dose-dependent manner. These findings highlight the potential of CuNPs as promising therapeutic agents for the treatment of lung adenocarcinoma. Additionally, CuNPs synthesized from Erioglossum rubiginosum leaves exhibit potent antioxidant properties, which may further contribute to their anticancer efficacy by mitigating oxidative stress in tumor microenvironments [193]. Traditional plant-based medicines have shown promising anticancer properties in lung cancer treatment. Research on medicinal plants for lung cancer has been conducted globally, with significant contributions from China, Japan, South Korea, and Ethiopia [194]. Various plant-derived compounds exhibit anticancer effects through mechanisms such as induction of apoptosis and inhibition and prevention of angiogenesis [195]. Specific phytochemicals, such as hispidulin, erianin, and albanol B, have demonstrated efficacy both in vitro and in vivo. Plant extracts, such as those from Marsdenia tenacissima, exhibit potent inhibition of lung cancer cells [196]. Network pharmacology and integrative omics approaches have identified bioactive compounds, such as luppeol and p-coumaric acid, that exhibit cytotoxicity against lung adenocarcinoma cells [197]. These natural compounds can sensitize cancer cells to chemotherapeutic drugs, extend patient survival, and improve quality of life while reducing side effects [198]. To enhance lung cancer treatment, it is imperative to explore novel combination strategies that integrate traditional Chinese medicine (TCM) with conventional chemotherapy regimens. Pre-treatment with Sun-Bai-Pi extract (SBPE) followed by cisplatin has been shown to induce autophagy in lung cancer cells. The combination of SBPE or Buzhong Yiqi decoction (BZYQD) with chemotherapeutic agents improves efficacy, reduces treatment duration, and decreases drug dosage. Additionally, LQ, another TCM compound, has demonstrated antitumor, anti-metastatic, and anti-angiogenic effects comparable to those of standard chemotherapy, but with minimal toxicity. Notably, LQ selectively targets cancer cells while sparing normal cells. These findings underscore the potential of TCM-chemotherapy combinations as safer and more effective treatment strategies, meriting further investigation in both preclinical and clinical settings [39,199,200,201]. Overall, plant-based bioactive compounds remain a rich source of potential anticancer agents for lung cancer treatment.

12. Therapeutic Strategies and Challenges in Modulating the Tumor Microenvironment in Lung Cancer

The malignant features of cancer cells cannot be understood without appreciating the crucial interplay between cancer cells and their local environment. Angiogenic vascular cells, lymphatic endothelial cells, immune cells, and cancer-associated fibroblasts are components of tumor infiltration, which actively leads to cancer progression. The efficient alteration of these surroundings is a crucial feature by which tumor cells can gain some of the hallmark functions necessary for tumor development and metastatic dissemination. Targeting the tumor microenvironment to encapsulate or destroy cancer cells in their local environment has become an important aspect of treatment. The differences in stromal cells, the complexity of the molecular elements of the tumor stroma, and the resemblance to normal tissue present huge challenges for therapies targeting the tumor microenvironment. The most recent investigations have shed light on the significant role of the noncellular stromal compartment composed of the extracellular progression [202]. To effectively address non-small cell lung cancer (NSCLC), it is imperative to employ a range of therapeutic strategies, particularly combination therapy. Nanostructured lipid carriers (NLCs) loaded with PTX and DOX have demonstrated enhanced cytotoxicity in vitro and significant tumor-targeting and antitumor effects in vivo compared with NLCs containing a single drug. Although EGFR tyrosine kinase inhibitors (TKIs) have revolutionized treatment for patients with EGFR mutations, resistance, both EGFR-dependent and -independent, continues to pose substantial challenges. The integration of RNA-based therapeutics with conventional cisplatin chemotherapy has shown promising survival benefits in preclinical models. These findings highlight the necessity of integrated multimodal treatment approaches that combine cytotoxic agents, targeted therapies, and RNA-based interventions to overcome resistance and enhance patient outcomes [203,204,205]. The TME influences the therapeutic effect/response and has an impact on the explicit surface receptors and activated or silenced signaling pathways. To address oncological issues such as lack of response to therapy, tumor resistance, and direct personalized medicine, each tumor must be considered a complex disease, different in each patient, and thus demanding a different therapeutic strategy, especially centered on combinations. Hence, to formulate new therapeutic strategies for more effective targeting of the TME, a significant attempt has been made, which centers on (i) therapeutic strategies that target TME components and (ii) the development of models that correspond to the TME for bench investigations [206]. It is now progressively accepted that cancer cells act intimately with the extracellular matrix (ECM) and stromal cells, which together form the major construct of the TME, instead of working alone [207].

13. Conclusions

The progression and malignancy of lung cancer cannot be fully understood without considering the intricate interplay between cancer cells and their surrounding tumor microenvironment (TME), comprising vascular, lymphatic, immune, and fibroblastic components. Tumor cells exploit this dynamic environment to acquire hallmark capabilities essential for growth and metastasis. Targeting the TME has therefore become a central focus in modern oncology, though challenges persist due to its cellular complexity, molecular diversity, and resemblance to normal tissue. Recent studies emphasize the critical role of the extracellular matrix (ECM) in tumor progression. In non-small cell lung cancer (NSCLC), combination therapies—including nanostructured lipid carriers (NLCs) co-loaded with chemotherapeutics, EGFR inhibitors, and RNA-based treatments—have shown promising potential to overcome drug resistance and improve clinical outcomes. Personalized therapeutic strategies that consider the unique TME profile of each tumor are essential. Current efforts are directed towards developing both targeted interventions and accurate TME-representative models for translational research. It is now widely recognized that cancer cells function not in isolation, but in close association with ECM and stromal cells, making the TME a critical target for future lung cancer therapies.

Author Contributions

Conceptualization: I.M. and M.M.H.; writing—original draft preparation: S.M.S., S.N.T. and M.A.-I.I.; review and editing: S.M.S., S.N.T., M.A.-I.I., M.M., F.A., M.A.M., I.M. and M.M.H. All authors have read and agreed to the published version of the manuscript.

Funding

This study received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

The following abbreviations are used in this manuscript:
NSCLCNon-small cell lung cancer
SCLCSmall cell lung cancer
TMETumor microenvironment
ICBImmune checkpoint blockade
MSCsMesenchymal stromal/stem cells
TAFsTumor-associated fibroblasts
TregsRegulatory T cells
MDSCsMyeloid-derived suppressor cells
NKNatural killer cells
DCsDendritic cells
ECMExtracellular matrix
HIFsHypoxia-inducible factors
MMPsMatrix metalloproteinases
MHCMajor histocompatibility complex
ICIImmune checkpoint inhibitors
TILTumor-infiltrating lymphocyte
CAFsCancer-associated fibroblasts
MDSCsMyeloid-derived suppressor cells
TAMsTumor-associated macrophages

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Figure 2. Stromal cells, including CAFs, MSCs, CAAs, TECs, and PCs, establish complex signaling networks that regulate tumor development, growth, and resistance to treatment. The figure is reprinted from Zhao et al. 2023 with free reuse permission [60].
Figure 2. Stromal cells, including CAFs, MSCs, CAAs, TECs, and PCs, establish complex signaling networks that regulate tumor development, growth, and resistance to treatment. The figure is reprinted from Zhao et al. 2023 with free reuse permission [60].
Futurepharmacol 05 00034 g002
Table 1. Major tumor-infiltrating immune cells observed in the lung cancer tumor microenvironment, their main roles, and their relationships with clinical outcomes.
Table 1. Major tumor-infiltrating immune cells observed in the lung cancer tumor microenvironment, their main roles, and their relationships with clinical outcomes.
Immune Cell TypeMain Function in TMEClinical/Prognostic Association
CD8+ T cellsCytotoxic killing of tumor cellsImproved survival, better ICI response [19,20]
CD4+ T cellsHelper/regulatory roles; coordinate immune responsesVariable; subset-dependent [20,21]
Regulatory T-cells (Tregs)inhibit anti-tumor immunityPoorer prognosis [20,22]
B cellsAntibody production, antigen presentationMixed; high density may predict HPD [19,23]
Macrophages (M1/M2)M1: pro-inflammatory/anti-tumor; M2: immunosuppressiveM1: favorable; M2: poor prognosis [20,21,22]
Myeloid-derived suppressor cells (MDSCs)Inhibit T-cell function, promote tumor growthPoorer prognosis [20]
Natural Killer cells (NKs)Direct killing of tumor cells (innate immunity)Generally favorable [21]
Dendritic cells (DCs)Antigen presentation, T-cell activationIt can be immunosuppressive in TME [22]
Mast cellsModulate inflammation, angiogenesisPrognostic value in LUAD [21]
Table 2. Basic characteristics and functions of cytokines [31,33].
Table 2. Basic characteristics and functions of cytokines [31,33].
CytokinePrimary SourceSusceptible CellsPrimary Function
IL-1Macrophages, monocytes, fibroblastsEndothelium, hypothalamus, T/B cellsCo-stimulation, inflammation, fever
IL-2T cells, NK cellsT/B/NK cells, monocytesGrowth and activation of immune cells
IL-4T cellsT/B cellsTh2 differentiation, IgE switching
IL-6Macrophages, T cellsT/B cells, liverAcute phase response, inflammation
IL-10Th2 cellsMacrophages, T cellsAnti-inflammatory, suppresses APCs
IL-12NK cells, macrophagesT cellsPromotes Th1 differentiation
IL-17NKT cells, ILCsEpithelial, endothelial cellsInflammation, infection control
IL-21CD4+ T cells, NKT cellsT/B/NK cellsEnhances immune responses
IL-23APCsT cells, NK cellsPromotes chronic inflammation via Th17
IFN-γT, NK, NKT cellsMonocytes, endothelial cellsMHC upregulation, macrophage induction
TNF-αT cells, macrophagesImmune, endothelial, liver cellsInflammation, fever, acute-phase response
TGF-βT cells, macrophagesT cellsSuppresses immune activation
IL-35TregsT cellsImmunosuppressive, induces iTr35
IL-37DCs, MonocyteMacrophages, B cellsDampens excessive inflammation
Table 3. Cytokines with their source and functions [97].
Table 3. Cytokines with their source and functions [97].
CytokineSourceFunctions
IL-6T cells, adipocytes, macrophagesProinflammatory action, promotes differentiation and cytokine production
IL-8Macrophages, epithelial cells, endothelial cells.Proinflammatory action, promotes angiogenesis and chemotaxis
IL-10Monocytes, B cells, T cellsAnti-inflammatory action, inhibits proinflammatory cytokines
IL-17Th17 cellsProinflammatory action, enhances cytokine and chemokine production, contributes to antitumor immunity
IL-27Antigen-presenting cells (APCs)Anti-inflammatory action, induces IL-10 production
IL-35Regulatory T cells (Tregs)Anti-inflammatory action, promotes Treg proliferation, suppresses Th17 cells
IL-37NK cells, monocytes, epithelial cells, B cellsAnti-inflammatory, antimicrobial, and contributes to antitumor immunity
TNF-αMacrophages, CD4+ lymphocytes, adipocytes, NK cellsProinflammatory action, induces cell proliferation, cytokine production, and apoptosis
IFN-γNK cells, T cellsAntiviral and proinflammatory action
TGF-βT cells, macrophagesAnti-inflammatory action, suppresses proinflammatory cytokine production
Granulocyte-macrophage colony-stimulating factor (GM-CSF)T cells, macrophages, fibroblastsProinflammatory action, enhances neutrophil and monocyte function, activates macrophages
Vascular endothelial growth factor (VEGF)Macrophages, endothelial cells, plateletsPromotes vasculogenesis, angiogenesis, endothelial chemotaxis, and migration
Table 4. microRNA expression status in lung cancer.
Table 4. microRNA expression status in lung cancer.
microRNATargetsExpression Status
(Underexpressed/Overexpressed/
Unchanged)
Comments
(If Any)
Reference
miR-487bSUZ12,BM11, MYCOverexpressedTumor suppressor Xi et al., 2013 [165]
miR-449HDAC1Overexpressed AM Rusek et al., 2015 [166]
miR-101EZH2Overexpressed AM Rusek et al., 2015 [166]
miR-486IGF1RUnderexpressedNSCLC tumor suppressorC M. Croce et al., 2013 [167]
miR-9MHC 1 geneOverexpressed AM Rusek et al., 2015 [166]
miR-124aCDK6OverexpressedTumor suppressorA Lujambio et al., 2007 [168]
miR-221TIMP3Overexpressed AM Rusek et al., 2015 [166]
miR-222TIMP3Overexpressed AM Rusek et al., 2015 [166]
miR-429ZEB1/2OverexpressedNSCLC oncogenicWu Cl et al., 2018 [169]
miR-128bEGFR in NSCLCUnderexpressedTumor suppressorBecker-Santos DD et al., 2012 [170]
miR-1827SK-LU-1, RBX1 in NSCLCUnderexpressedNSCLC tumor suppressorSM Noor et al., 2018 [171]
miR-378RBX1, CRKL in NSCLCOverexpressedNSCLC tumor suppressorSM Noor et al., 2018 [171]
miR-630Mut-Bcl-2–3′-UTRUnchangedNSCLC tumor suppressorHuei Lee et al., 2018 [172]
miR-31LATS2/PPP2R2AOverexpressedNSCLC oncogenicLiu et al., 2010 [173]
miR-221/222PUMAOverexpressedNSCLC oncogenicZhang et al., 2010 [174]
miR-197PD-L1OverexpressedNSCLC oncogenicFujita et al., 2015 [175]
microRNA-146aEGFROverexpressedNSCLC tumor suppressorChen et al., 2013 [176]
Table 5. Role of the tumor microenvironment and of the different cell populations.
Table 5. Role of the tumor microenvironment and of the different cell populations.
Cell TypesIn the Progression of Lung Cancer In the Induction of the EMT ProcessIn the Development of Anticancer Drugs Resistance
Tumor-infiltrating lymphocytes (TILs)Positive correlation and high levels are associated with better overall survival [24,177]Induce epithelial–mesenchymal transition (EMT) [178]Resistance to anti-tumor immunity [179]
Cancer-associated fibroblasts (CAFs)Enhancing the plasticity and self-renewal capabilities of CSCs [58]Induce epithelial–mesenchymal transition (EMT) [180]Support cancer cell survival in the presence of anticancer drugs [181]
Mesenchymal stem cells (MSCs)Promote tumor metastasis and tumorigenesis [182]Induce epithelial–mesenchymal transition (EMT) [182]Play a significant role in cancer progression and drug resistance [183]
Tumor endothelial cells (TECs)Cancer progression by supporting angiogenesis and metastasis [184]Crucially engage the hypoxia-triggered epithelial-to-mesenchymal transition (EMT) [185]Contribute to drug resistance in cancer therapy [186]
Regulatory T cells (Tregs)Interact with cancer stem cells (CSCs) and contribute to tumor relapse [187]Promote epithelial-mesenchymal transition (EMT) [188]Play a crucial role in cancer treatment resistance [189]
Tumor-associated macrophages (TAMs)Support cancer stem cells (CSCs) and promotes lung cancer progression [190]Induce epithelial–mesenchymal transition (EMT) [191]Promote drug resistance in cancer treatment [192]
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Sohag, S.M.; Toma, S.N.; Imon, M.A.-I.; Maihemuti, M.; Ahmed, F.; Mimi, M.A.; Mahmud, I.; Hasan, M.M. Tumor Microenvironment: An Emerging Landscape for Lung Cancer Therapy. Future Pharmacol. 2025, 5, 34. https://doi.org/10.3390/futurepharmacol5030034

AMA Style

Sohag SM, Toma SN, Imon MA-I, Maihemuti M, Ahmed F, Mimi MA, Mahmud I, Hasan MM. Tumor Microenvironment: An Emerging Landscape for Lung Cancer Therapy. Future Pharmacology. 2025; 5(3):34. https://doi.org/10.3390/futurepharmacol5030034

Chicago/Turabian Style

Sohag, S. M., Sharmin Nur Toma, Md. Al-Imran Imon, Maiweilan Maihemuti, Famim Ahmed, Mst. Afsana Mimi, Imran Mahmud, and Md. Mahmudul Hasan. 2025. "Tumor Microenvironment: An Emerging Landscape for Lung Cancer Therapy" Future Pharmacology 5, no. 3: 34. https://doi.org/10.3390/futurepharmacol5030034

APA Style

Sohag, S. M., Toma, S. N., Imon, M. A.-I., Maihemuti, M., Ahmed, F., Mimi, M. A., Mahmud, I., & Hasan, M. M. (2025). Tumor Microenvironment: An Emerging Landscape for Lung Cancer Therapy. Future Pharmacology, 5(3), 34. https://doi.org/10.3390/futurepharmacol5030034

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