From Incision to Immunity: Integrating Surgery and Immunotherapy in Non-Small Cell Lung Cancer

Abstract

Lung cancer is the most common cause of death due to cancer in the world, and non-small cell lung cancer (NSCLC) is the most common form of lung cancer, representing approximately 84% of all cases. Due to its frequency and mortality, the amount of research on this subject has been greatly increased and new techniques to improve health outcomes have been established. While surgery remains the gold standard of treatment, immunotherapy used alone or in conjunction with surgery shows promising results. This review aims to give an overview of current and new surgical and immunotherapy methods used for the treatment of NSCLC, as well as ways in which they can be combined and the clinical outcomes for patients with each treatment modality. Additionally, it will seek to highlight any gaps in current knowledge of treatment and propose further studies to improve the efficacy of NSCLC treatments.

1. Introduction

Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers and remains the leading cause of cancer mortality worldwide despite advances in detection, surgical resection, and systemic therapy [1]. Immunotherapy approaches have recently become one of the most widely used systemic treatments for NSCLC [2]. In NSCLC, immunotherapy is often used alongside surgery to reduce tumor size before resection or to eliminate malignant disease [3]. These limitations have led to growing interest in combining chemotherapy with newer treatments, such as immunotherapy and targeted agents, to enhance overall outcomes [4,5]. Immunotherapeutic agents including PD-L1, PD-1, and CTLA-4 inhibitors form a cornerstone in the treatment of late-stage NSCLC, functioning to reduce tumor burden, improve overall survival, and generally help control metastatic disease [4].

Another approach to treating NSCLC is surgical resection, which remains the primary curative approach for early-stage, centrally located, and locally advanced NSCLC [5,6,7,8]. While surgical management has shown promise, long-term survival often remains suboptimal, in part due to recurrence driven by micrometastic spread [5]. These malignant cells are a major cause of relapse, even in patients whose NSCLC is detected in the early stages [9].

This has driven the evolution of multimodal treatment strategies and personalized medicine, combining surgery with systemic therapies, such as chemotherapy, immunotherapy, and targeted agents, to optimize outcomes [10,11,12,13,14,15]. While encouraging progress has been made, challenges still remain in refining treatment selection, minimizing toxicity, and improving access to these integrated approaches, underlining the clinical importance of research in this area [16,17,18,19,20].

This study focuses on a range of systemic agents being explored in combination with surgery for NSCLC. These include immune checkpoint-targeting therapies such as programed cell death receptor 1 (PD-1) inhibitors, Programed cell death receptor ligand 1 (PD-L1) inhibitors, and Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) inhibitors, as well as targeted therapies that act on specific genetic drivers of NSCLC [19]. Tyrosine kinase inhibitors are also discussed, which disrupt signaling pathways critical to tumor growth [21]. While each of these classes has distinct mechanisms and clinical considerations, their shared goal is to improve outcomes when integrated into the surgical treatment.

This study synthesizes previous research on integrating immunotherapy with surgical management in NSCLC, examines emerging perioperative strategies, and highlights unresolved clinical questions to guide future research and clinical practice. By consolidating the latest data and identifying knowledge gaps, this study aims to inform both oncologic and surgical decision-making and ultimately contribute to improving survival and quality of life for patients with resectable NSCLC.

2. Literature Search Strategy

This study was developed to summarize current evidence on the management of NSCLC, with emphasis on immunotherapy, immunotherapy resistance, surgical management, personalized medicine, and the role of a multidisciplinary team. Relevant literature was identified through searches of PubMed for English language articles published up to September 2025. Search terms included combinations of keywords related to NSCLC and its management such as “non-small cell lung cancer”, “Immunotherapy”, “treatment resistance”, “surgery”, and “multidisciplinary approach”. Additional references were obtained by reviewing the reference lists of key publications and major reviews to ensure comprehensive coverage of recent advances. Articles were included based on relevance, quality, and contribution to the understanding of NSCLC management. Case reports, conference abstracts, and non-peer-reviewed studies were excluded.

3. Immunotherapy

3.1. Approved Immunotherapeutic Agents

Currently the use of immunotherapeutic agents is the first-line treatment for stage IV NSCLC [22,23]. Immunotherapy is also utilized as an adjunct treatment in stage IIIB or nonresectable stage III NSCLC [22,23]. Some of the most prevalent immunotherapies target cell checkpoints. These include PD-1, PD-L1, and CTLA-4 inhibitors [24].

Choosing the correct immunotherapeutic agent for the treatment of NSCLC is dependent on the mutations present in the malignant cells [25]. PD-1/PD-L1 inhibitors see the most benefit when used with malignancies that have a PD-L1 expression above 50% [25]. CTLA-4 inhibitors are more useful when the malignant cells have low or negative expression of PD-L1 [26,27]. In patients with low or negative PD-L1 expression it is commonplace to use both CTLA-4 inhibitors in conjunction with a PD-1 inhibitor [24,26,27]. CTLA-4 inhibitors act directly on the T-cells found in lymphoid tissue and not directly on the malignant cells. With direct activation of T-cells it is common for the CTLA-4 inhibitors to cause more systematic effects and increases the risk of severe systemic effects [24,26].

3.2. PD1/PD-L1 Inhibitors/Antibodies

PD-1 and PD-L1 inhibitors are both monoclonal antibodies that act as immune checkpoint inhibitors, as seen in Table 1 [4,28]. These antibodies act by binding their respective receptor/ligand and inactivating them, allowing the activation of T-cells [4,28]. Some of the anti-PD1 pharmaceuticals currently on the market include pembrolizumab and nivolumab [4,28]. The anti PD-L1 pharmaceuticals include atezolizumab, aurvalumab, and avelumab [4,28].

Table 1. Summary of immunotherapeutic agents for NSCLC.

Immunotherapeutic Class	Mechanism of Action	Survival	Limitations	Ref.
PD-1 Inhibitors	Immunoglobins directly inhibit PD-1 receptors on T-cells, which generates an immune response	OS saw a 13-month improvement when compared to chemotherapy	Cannot be used when PD-L1 expression is low	[4,28,29,30]
PD-L1 inhibitors	Immunoglobins directly inhibit PD-L1 on malignant cells, which generates an immune response	OS HR of 0.85 when compared to chemotherapy	Cannot be used when PD-L1 expression is low	[4,28,29,30]
CTLA-4 inhibitors	Immunoglobulins directly inhibit CTLA-4 receptors on T-cells, allowing T-cell activation and the initiation of an immune response against malignant cells	PFS HR of 0.75 compared to chemotherapy	Can cause system-wide reactions	[4,24,26,27,31]

3.2.1. PD-1/PD-L1 Mechanism of Action

PD-1 receptors are found on macrophages, T-cells, B-cells, natural killer T-cells, and dendritic cells [4,29], while PD-L1s are found on the majority of immune and non-immune cells in the body [4,29]. Normally this pathway is a self-regulatory mechanism to prevent excess activation of T-cells and potentially cause autoimmune dysfunctions [4,29]. The binding of PD-1 to PD-L1 inhibits transcription factors that lead to immune response activation [4,29]. PD-1/PD-L1 inhibitory agents act on this pathway to allow T-cell activation to occur, allowing an immune response to be propagated against the malignant cells [4,29].

The PD-1/PD-L1 interaction is an immune checkpoint pathway that is commonly exploited by tumors to suppress the activation of T-cells [4,29]. Commonly, tumor cells evade detection from the immune system by expressing large amounts of PD-L1 on their membrane [4,29]. This allows the tumor cells to bind PD-1 and prevent the activation of the immune system [4,29]. The inhibition of the PD-1/PD-L1 checkpoint is the mechanism by which therapies can alter the response of the immune system to target NSCLC [4,29].

3.2.2. PD-1/PD-L1 Outcomes

The use of PD-1 and PD-L1 inhibition is relatively new in the treatment of late-stage NSCLC, with pembrolizumab (PD-1 inhibitor) becoming approved in 2016 as the first-line treatment of metastatic NSCLC [30]. As previously mentioned, the primary use of immunotherapy is in the late stages of NSCLC [32,33,34]. This includes NSCLC stage IV and nonresectable stage III [32,33,34].

A systematic review performed by Roussos and Migkou looked at the use of PD-1 and PD-L1 inhibitors specifically in stage III NSCLC [34]. This reviewed both the use of the inhibitors as monotherapy as well as an adjunct with chemotherapy [34]. The results from this study were reported in overall survival (OS), progression free survival (PFS), event-free survival (EFS), and disease-free survival (DFS) [34]. They found that the use of these inhibitors improved both OS and PFS [34]. Hazard ratios (HRs) and risk ratios (RRs) were utilized to measure the effectiveness of the treatments [34]. OS was improved when given as monotherapy after chemotherapy with an HR recorded at 0.85 [34]. PFS also saw improvements in these groups with an RR being reported at 0.75 [34]. When using PD-1 inhibitors in conjunction with chemotherapy, the OS improvement was recorded as having an RR of 0.40; PFSs were not recorded in these specific trials [34].

Wu et al. completed a meta-analysis on the use of PD-1/PD-L1 inhibitors as a monotherapy for stage IIIB and IV NSCLC [33]. In this analysis, chemotherapy was used as a comparison against the PD-1/PD-L1 inhibitors [33]. This trial also looked at measures of OS and PFS and reported data in terms of hazard ratio [33]. When observing OS, the reported HR was 0.71, and for PFS, it was 0.88 [33]. Overall, this study found that when compared to chemotherapy, the use of PD-1/PD-L1 inhibitors was more effective in treatment of late-stage NSCLC [33].

Similarly, a study performed by Reck et al. compared the outcomes of providing pembrolizumab (PD-1 inhibitor) vs. platinum base chemotherapeutic agents as monotherapy for stage IV NSCLC [25]. The outcomes that were focused on in this study were OS and PFS, reported as HR [25]. When compared to PFS, it had a reported HR of 0.50 and OS had a reported HR of 0.60 [25]. At the end of the trial the group on chemotherapy had a reported median OS of 13.4 months while the group using pembrolizumab had a median OS of 26.3 months [25]. Overall, this study showed that the use of PD-1 inhibitors significantly improved the OS and PFS when compared to chemotherapy in stage IV NSCLC [25].

3.3. CTLA-4 Inhibitors/Antibodies

CTLA-4 inhibitors are monoclonal antibodies that act to negatively regulate the activity of T-cells and are classified as immune checkpoint inhibitors, as seen in Table 1 [4,27]. Commonly, CTLA-4 inhibitors are used in stage IV NSCLC, where the cancer cells have a low or negative expression of PD-L1 [24,26,27]. When CTLA-4 inhibitors are used, they are typically used in conjunction with a PD-1 inhibitor and rarely used as a monotherapy [24,26,27]. The primary therapeutic agent being used as a CTLA-4 inhibitor in NSCLC is typically ipilimumab or tremelimumab [4,27].

3.3.1. CTLA-4 Mechanism of Action

A primary way that T-cells are active is through stimulation of T-cell receptors (TCRs) [4]. For activation of T-cells to occur the TCR must bind with an antigen-presenting cell (APC) via the MHC complex [4]. Along with the TCR, T-cells also have CTLA-4 and CD28, both of which competitively bind for the B7 ligand on the APC [4]. These act as co-stimulatory signals necessary for full activation of the T-cell; CD28 acts to stimulate the T-cell when bound while CTLA-4 acts to inhibit activity [4]. Normally, this mechanism helps regulate the immune response and prevent excessive activation [4]. Blocking this mechanism from occurring is the reasoning for utilizing CTLA-4 inhibitors [4]. The use of CTLA-4 inhibitors shows promise in the treatment of late-stage NSCLC because the inhibitor primarily acts on the T-cells themselves instead of directly on malignant cells, which makes adaptation by malignant cells difficult [4]. The mechanism of action for the mentioned ICIs is visually depicted in Figure 1.

Figure 1. Shows the mechanism of action of immune checkpoint inhibitors. Created in BioRender, version 1.0.0.5; Science Suite Inc.: Toronto, ON, Canada, 2025. https://BioRender.com/edjus7i (accessed on 13 October 2025).

3.3.2. CTLA-4 Outcomes

The clinical use of ipilimumab (CTLA-4 inhibitor) in the treatment of late-stage NSCLC was first approved in 2020 [35]. In this approval, Ipilimumab was approved as a part of a combination therapy with nivolumab (PD-1 inhibitor) [35]. Since this approval, multiple studies have been performed showing its effectiveness and the approval of newer CTLA-4 inhibitors such as tremelimumab has been shown [31]. Combination therapies involving PD-L1 inhibitors have also been shown to have possible effects in the treatment of late-stage NSCLC [31].

In 2022, Johnson et al. published a study reviewing the effectiveness of using a combination therapy of tremelimumab (CTLA-4 inhibitor) and durvalumab (PD-L1 inhibitor) [31]. In this study the combination of the CTLA-4 and PD-L1 inhibitors was compared to both a monotreatment of chemotherapy and a combination treatment of chemotherapy, tremelimumab, and durvalumab [31]. These therapies were used in the treatment of stage IVa and IVb NSCLC [31]. When compared to monotherapy, the combination of durvalumab and tremelimumab group showed a significant improvement in PFS with a reported HR of 0.75 [31]. While OS was not statistically significant, the study did note that a trend of improvement was seen [31]. The combination therapy of tremelimumab and durvalumab showed statistically significant improvement in PFS when compared to the chemotherapy group [31].

In a phase 3 trial reported by Hellmann et al., the combination therapy of nivolumab (PD-1 inhibitor) and ipilimumab (CTLA-4 inhibitor) for the treatment of stage IV NSCLC was evaluated [36]. The results in this study were reported as OS in months and PFS, and the therapy was compared to standard chemotherapy usage alone [36]. When comparing chemotherapy alone to the combination therapy of nivolumab and ipilimumab, the OS reached a statistically significant improvement, being 14.9 vs. 17.1 months, respectively [36]. In this arm of the study the patient’s malignant cells had a PD-L1 expression over 1% [36]. Another arm of the study observed patients with a PD-L1 expression under 1% using the same treatment comparison [36]. Here the combination therapy saw an OS of 17.2 months while the chemotherapy treatment alone saw 13.9 months [36]. For PFS the researchers looked again at the combination therapy vs. chemotherapy alone, finding that PFS was significantly higher at two years with the survival being reported as 10.5% and 4.6%, respectively [36].

3.4. Immunotherapy Resistance

Immunotherapy is an excellent avenue for treating NSCLC, but a major concern for future treatments is drug resistance. Immune checkpoint inhibitor (ICI) response rates vary heavily from study to study, with some finding results as low as 8%, and this resistance can be primary or acquired over time [37]. Primary resistance is a lack of initial response to immunotherapy, occurring in 21–27% of NSCLC patients when used as first-line therapy, although this can decrease to 10% when ICIs are combined with chemotherapy. As a second-line therapy, primary resistance to ICI can increase to 40–44% [38]. Acquired resistance is seen when patients initially respond to immunotherapy but see the treatments lose efficacy later. Acquired is more common than primary, with rates of 52–57% for first-line patients and 32–64% for second line [39]. The mechanisms of this resistance are multifaceted but can generally be attributed to genetic mutations of the tumor, immunosuppressive effects of the tumor microenvironment, and exacerbation of comorbidities such as COPD [37]. This resistance can potentially be reduced by nanomedicine, targeting of tumor cell-associated signaling pathways and immune checkpoints, and specific inhibition of immune cells with pro-tumor effects, such as tumor-associated macrophages and myeloid-derived suppressor cells [40].

Social factors, such as smoking, can also play a role in reducing response rates. Interestingly, a study by Sun et al. found that smoking positively affects progression-free survival, with an HR of 0.69, 95% CI 0.49–0.97. This was hypothesized to be related to the smoking group’s stronger microenvironment and higher immunogenicity, along with greater infiltration of immune-activated cells rather than immunosuppressive cells such as regulatory T-cells [41]. While perhaps confounding, this finding, if substantiated, may prove beneficial due to the correlation between smoking and NSCLC. Obesity is another social factor which has been correlated with poorer prognoses in cancer, but surprisingly ICIs in obese patients may have stronger therapeutic benefits than in non-obese patients, potentially due to interactions with lipid metabolism [42]. Conversely, Martin-Ruiz et al. displayed increased efficacy of ICIs with exercise in mouse models [43]. Based upon these results, it is likely that there are further lifestyle modifications that could be identified to reduce resistance to treatment of NSCLC with immunotherapy.

As research in the field of immunotherapy grows, drug resistance will become an ever-greater problem. With trials of chemotherapy seeming to reduce primary resistance and lower levels of resistance when ICIs are used as first-line therapy, studies could be designed to find the best combination of drugs to utilize. Additionally, social and environmental factors which may decrease resistance have truly had little examination. Identification of advantageous lifestyle modifications could aid in increasing the likelihood of a successful treatment.

3.5. Overcoming Immunotherapy Resistance

Recent studies have found a multitude of methods to combat resistance to immunotherapy treatment. These range from combination therapies to early detection and immune reactivation. Combination therapy is the practice of utilizing more than one treatment strategy at a time, often displaying synergistic effects in comparison to monotherapy. Immunotherapy is commonly started alongside chemotherapy with noted benefits. Additionally, a second immunotherapeutic agent can enhance efficacy of both drugs. PD-L1 and CTLA-4 are commonly targeted sites which may be focused on simultaneously with positive outcomes, as shown in melanoma, renal cell, colorectal, hepatocellular, and esophageal carcinoma [44]. In NSCLC, dual ICI therapy has shown significant results, with increased OS regardless of PD-L1 expression, although this effect was especially pronounced in patients with a high tumor mutational burden [44]. A 2024 study on 5-year outcomes of metastatic NSCLC showed a greater OS with nivolumab (anti-PD-L1) and ipilimumab (anti-CTLA-4) alongside chemotherapy compared to solely chemotherapy (18% vs. 11%, HR 0.73). This result was consistent regardless of tumor PD-L1 expression [45]. While the combination of ICIs may provide a method of evading tumor resistance, it can also cause an increased incidence of grade 3/4 adverse effects, and as such will need to be monitored, particularly in conjunction with treatments such as chemotherapy and radiation, which may exacerbate these effects [44].

While dual ICI treatments remain effective, bispecific antibodies (bsABs) may provide similar outcomes while reducing treatment-related toxicities [44]. A 2023 phase 1/2 trial on cadonilimab’s (bispecific PD-1/CTLA-4 antibody) effect on advanced solid tumors found an objective response rate as high as 32.3% in cervical cancer and as low as 16.7% in hepatocellular cancer [46]. In lung cancer, cadonilimab has been tested in patients who failed chemotherapy and resisted immunotherapy. Results were disappointing, with no results found in groups where patients had previously displayed acquired or primary resistance to immunotherapy [47]. Multiple trials are currently ongoing to determine if these results are the rule or the exception [44].

While this lack of success may be disheartening, new antibodies are being developed targeting specific markers which differ from the standard treatments. Amivantamab, which binds epidermal growth factor receptor (EGFR) and messenchymal epithelial growth factor, consistently lowered the HR for death when compared to chemotherapy alone and had consistently elevated overall response rates [48]. Zenocutuzumab, which binds HER2 to modify HER3, displayed overall response rates of 29% in NRG1 fusion-positive NSCLC, a notoriously resistant version of lung cancer [49]. Ivonescimab, which binds PD-1 and vascular endothelial growth factor, achieved overall response rates of 50.6% in conjunction with chemotherapy compared to 35.4% for solely chemotherapy [50]. These results indicate that tumor resistance may be mitigated through careful selection of treatment targets.

Early detection and analysis of tumors is another way to reduce resistance as the cancer will have had less time to grow and adapt, and more specific therapies can be started earlier on. Circulating tumor DNA (ctDNA) has become one of the most reliable markers of disease in most forms of cancer, and is more convenient, safe, and cost-effective, along with providing quicker turn around times for diagnosis [48,51]. Liquid biopsies like those performed for ctDNA do not require biopsy of the tumor in the lung, subjecting the patient to far less stress and can be repeated throughout treatment, allowing for accurate monitoring of the results of immunotherapy [52]. While the sensitivity remains problematic, a 2023 meta-analysis determined that methylated ctDNA had a 92.9% specificity in lung cancer, making it a potentially valuable tool to rule in NSCLC [53]. This value only increases due to the large proportion of patients which are diagnosed after the cancer has progressed past localized stages, as the relative ease of the test could make it a valuable screening tool. There are challenges which need to be addressed however, including the simple fact that ctDNA is seen in greater amounts when the tumor is larger, meaning ctDNA is at its lowest in the early stages of the disease when identification would lead to the best outcomes [50]. Besides early detection, minimal residual disease may be monitored with ctDNA, with Guo et al. finding that ctDNA positivity postoperatively led to poorer OS (HR 5.07), with survival benefits from adjuvant therapy (HR 0.30). In addition, ctDNA negative patients showed no significant improvement with adjuvant therapy, suggesting that ctDNA markers could provide benefit in guiding postoperative treatment [54]. In short, ctDNA could be a valuable tool to identify tumors early and slow the development of their tumor microenvironment while guiding treatment.

One of the major ways in which the tumor evades immunotherapy is through immune suppression. New treatments seek to reactivate the immune system and sensitize the cells to the tumor. Viral immunotherapy aims to do this by inflaming tumors, thereby increasing immune activation in the local area. They can do this through specific replication in tumor cells, oncolysis and release of inflammatory factors, or transgene expression for enhanced efficacy [55]. A 2025 meta-analysis determined that oncolytic virus therapy had an HR of 0.86 for OS and an odds ratio of 1.62 for overall response in intermediate to advanced solid tumors. One particular strain, T-VEC, showed greater response rates, although this was in melanoma, not NSCLC [56]. Another strain, CAN-2409, can be taken with valacyclovir to create a toxic metabolite within the tumor microenvironment. A phase II trial used this therapy with ICI in advanced NSCLC and found 65% of patients experienced tumor shrinkage of injected and uninjected lesions [57]. Generally speaking, the effects of virus therapy on NSCLC are clinically beneficial, although the effect on OS and response rate in NSCLC is unclear [55]. Further trials will be required to determine what virus strains and combination therapies are most effective.

While immunotherapy resistance remains a large issue to overcome, there are multiple avenues which can be explored to find solutions. Combinations of ICIs appear to offer greater results, while bsABs show benefits with lower side effects by targeting markers which may be more specific to NSCLC. ctDNA offers an excellent opportunity for early detection and monitoring to prevent relapse, while viral therapy can restart the local immune system. In all fields, further research specific to NSCLC is required.

4. Surgical Management

4.1. Role of Surgery in NSCLC

Currently the gold standard treatment for NSCLC in the early stages, defined as stages I and II, is surgical management, but this is also indicated in centrally and locally advanced NSCLC [6,7,8]. There are many different surgical approaches for NSCLC such as wedge resections, lobectomy, segmentectomy, and pneumonectomy [6,7,8,58,59,60,61,62,63,64,65,66,67]. Also, there are innovative approaches that are starting to become mainstream treatments such as video-assisted thoracic surgery (VATS) and robotic-assisted surgery (RATS), which are showing promising outcomes [68,69,70,71,72,73]. Figure 2 provides a visual description of these different forms of resection.

Figure 2. Different forms of surgery for NSCLC. Created in BioRender, version 1.0.0.5; Science Suite Inc.: Toronto, ON, Canada, 2025. https://BioRender.com/9itqfpi (accessed on 13 October 2025).

4.2. Surgical Procedures Options

4.2.1. Sublobar Resection

Sublobar resection encompasses two different procedure options, wedge resection and segmentectomy. These procedures are typically indicated for patients who are capable of undergoing a lobectomy but are electing not to in order to save more lung tissue, as sublobar resection ends up taking less lung tissue than lobectomies [6,8,58]. Furthermore, sublobar resections are also indicated for patients who have comorbidities or lackluster pulmonary function tests [6,8,58]. Current guidelines for sublobar resection in the surgical management of NSCLC indicated its use when the patient meets the following criteria: clinical stage IA, size less than 2 cm, a single tumor in the outer third of the parenchyma, NSCLC suspected, no lymph node metastasis, or C/T ratio <0.5 evaluated using a CT lung window [59,60].

Recently, a clinical trial looked at wedge vs. segmentectomy in patients with stage 1A [74]. In it, 262 patients underwent segmentectomy and 195 underwent wedge resection; they found that patients that underwent segmentectomy had a significantly lower cumulative incidence of recurrence [74]. However, wedge resection still has some notable benefits, the most prominent being preserved lobes. It was found that over two times the number of patients (9 vs. 5, respectively) were able to retain more lung tissue [74].

Next, recent clinical trials aimed to look at which approach, sublobar or lobectomy, was superior in terms of 5-year disease-free survival and five-year overall survival [59,75]. The trial enrolled stage 1A (T1aN0) patients with NSCLC to undergo either sublobar resection (340 patients) or lobar resection (357 patients) [75]. Additionally, as approach was not the goal of this study, the surgeon was able to choose from the following options: thoracotomy, VATS, or RATS [75]. The five-year disease-free survival was found to be 63.6% in the sublobar group compared to 64.1% in the lobar resection group [75]. Five-year overall survival was found to be 80.3% vs. 78.9% in the sublobar resection vs. lobar resection, respectively [75]. Additionally, forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) 6 months post operation were compared between the groups [75]. It was found that both FVC and FEV1 had a greater reduction in lobar resection (−5.0% and −6.0% respectfully) when compared to sublobar resection (−3.0% and −4.0% respectfully) [75]. While these values in populations with normal baseline pulmonary function are not clinically significant, they may be in populations who have abnormal pulmonary function, which supports the idea for further clinical trials [75].

The investigators were able to conclude that sublobar resection was noninferior when compared to lobar resection and that sublobar is an effective surgical management approach for stage 1A NSCLC [75]. Lastly, this study supports the idea that individuals with an already compromised pulmonary function test might benefit from sublobar over lobar as highlighted earlier [6,8,58,75].

Wedge Resection

Wedge resection, unlike its counterparts, is the nonanatomic removal of lung tissue, meaning that it is performed without ligation or dissection of the individual airways or vasculature [61]. Furthermore, a recent study which looked at the distance of resection (≤5 and >5 mm) in stage I solid tumor NSCLC found the five-year recurrence-free survival to be 24.2% and 79.6% respectfully [61,62]. As noted previously, one of the biggest benefits to this option is the amount of lung tissue that is preserved compared to other treatments. This, however, comes with a tradeoff, which is an increased risk of recurrence as mentioned above [6,58,74]. Lastly, there are three main approaches: open (thoracotomy), VATS, and RATS [71]. VATS and RATS will be discussed in detail later in this study.

Segmentectomy

While segmentectomy is categorized with wedge resection, it is a vastly different procedure [59]. Segmentectomy involves following anatomical barriers, which involves the dissecting of veins, arteries, and bronchi associated with the malignant segment [59]. Additionally, as discussed previously, new advancements such as VATS and RATS are starting to become the main line approach for surgical management [59].

A recent clinical trial aimed to determine if segmentectomy was superior when compared to lobectomy [76]. This phase 3 trial enrolled stage IA NSCLC patients into either the lobectomy (554 patients) or segmentectomy (552 patients) group [76]. The surgeries were performed either with or without VATS; RATS was not used in this trial [76]. The five-year overall survival and relapse-free survival was found to be 94.3% and 88% respectfully for segmentectomy and 91.1% and 87.9% respectfully for lobectomy [76]. Therefore, the investigators concluded that segmentectomy should be the standard surgical option for small-peripheral NSCLC [76].

4.2.2. Lobectomies

Historically, lobectomies were the gold standard for patients with early-stage NSCLC; however, they are starting to become a procedure of the past with new staging technology and approaches allowing healthcare teams to make better decisions than they did in the past [6,58]. They do remain the gold standard options for patients with centrally located NSCLC [63,64,77]. Lobectomies have three main subcategories, lobectomy, sleeve lobectomy, and extended sleeve lobectomy, which each has its own unique features [63,64,65]. The standard lobectomy is performed by simply removing the lobe that is malignant and all vascular associated with that specific lobe [66]. The classic sleeve lobectomy involves the removal of an entire lobe from the patient followed by end-to-end bronchial anastomosis [63]. Lastly, the extended sleeve lobectomy is similar to the sleeve lobectomy but removes more than one lobe from the patient, and rather than using end-to-end anastomosis, an atypical brachioplasty is utilized due to the removal of more than one lobe [63,65].

A recent study looked at the long-term survival of patients following extended sleeve lobectomy or pneumonectomy in patients with central NSCLC [63]. It was found that when the extended sleeve lobectomy was performed, the overall survival (HR 0.63) and disease-free survival (HR 0.57) were found to be significantly higher compared to the pneumonectomy. The investigators did note there were some limitations to this data in that none of it came from randomized control trials (RCTs) and that future research needs to be aimed at completing RCTs to see if the data is still representative [63].

Furthermore, a recent study that was published earlier this year looked at the long-term survival of patients who underwent either a sleeve lobectomy or a pneumonectomy [64]. Due to this trial being retrospective and not an RCT, they were able to match patient clinical presentations in order to control for external variables [77]. They found that individuals that underwent the sleeve lobectomy had a longer overall survival with a 0.55 HR at a 95% confidence interval [77]. They also found that five-year overall survival was 61% in the sleeve lobectomy compared to 42% in the pneumonectomy group [77]. They were able to conclude that the short-term mortality is similar between the procedure types and that sleeve lobectomy provided superior long-term survivability when compared to the pneumonectomy [77].

4.2.3. Pneumonectomy

Pneumonectomy involves the removal of either the left or right lung and all associated vasculature, with variation in the procedure depending on which lung needs to be removed and possible pericardial reconstruction, which will not be discussed in this study [7,67]. Importantly, pneumonectomies are not the preferred method of surgery for patients with central or locally advanced NSCLC. Lobectomies are, in part due to the acute loss of pulmonary function and cardiorespiratory load [7]. A recent study examined pneumonectomies and their outcomes; it should be noted that some of the patients were given neoadjuvant therapy (33 of 100 patients), and the rest (67 of 100 patients) were not given neoadjuvant therapy, although both groups did undergo pneumonectomies [7]. They found that patients with a lower stage of NSCLC had a higher 5-year overall survival, which was 71.4% stage I, 32.4% stage II, and 28.7% for stage III. Furthermore, it was found that there was no significant difference in 5-year overall survival between the neoadjuvant and non-neoadjuvant group (39.8% and 29.2% respectfully) [7]. While this initial trial does not display the desired results for neoadjuvant and surgical management, it will be discussed in more depth later in this study. Overall, it appears that pneumonectomies are still a very viable approach for central or locally advanced NSCLC. Future studies need to explore long-term survivability and integrate with chemoimmunotherapies.

5. Emerging Surgical Approaches

5.1. Video-Assisted Thoracic Surgery

Video-assisted thoracic surgery, known as VATS, is an alternative option to traditional thoracotomies [68]. VATS, which utilizes a small camera, allows the surgeon to have a more robust view of the anatomy compared to the traditional thoracotomies [73]. Some of the notable benefits of VATS compared to the traditional approach are its short hospital length of stay, lower estimated blood loss or transfusion rate, and fewer complications [68,69]. VATS is also being performed more frequently in part due to its minimally invasive approach [68]. A recent study aimed to explore VATS sleeve lobectomy compared to the traditional thoracotomy sleeve lobectomy [70]. The investigators were able to determine that VATS led to significantly shorter hospital stay time and blood loss [70]. Moreover, they found that VATS had similar three-year overall survival when compared to the traditional approach; however, it was noted that VATS led to a significant increase in operation time [70].

5.2. Robotic-Assisted Thoracic Surgery

While both VATS and RATS are front-line approaches for early-stage lung cancers, RATS has made significant advancements since its creation and as such has become increasingly popular [71,72]. One advantage of RATS over VATS is the 3D view RATS can provide, which allows the surgeon to have a more clear and detailed view of the anatomy. Additionally, RATS allows more dexterous and precise movements during the procedure [73]. A recent study explored RATS vs. VATS in wedge resection for patients with stage 1 NSCLC with a tumor ≤2 cm [71]. It was found there was no difference in 30-day readmission and no difference was found at the 30- and 90-day marks for survival [71]. Moreover, no difference was noted in positive resection margins [71]. One important finding from the study was that patients who underwent RATS were more likely to have lymph nodes examined and dissected when compared to VATS [71]. For this reason, the investigators were able to conclude RATS may hold some benefit over VATS due to the reason mentioned above [71].

Next, another recent study explored the possible benefits of VATS vs. RATS in lobectomies for patients with NSCLC [72]. This RCT had 320 patients which were divided into two groups, RATS (157 patients) and VATS (163 patients). The primary end point of 3-year overall survival was not reported on and to date no update has been released. No significant difference was found in postoperative hospital stay, intraoperative blood transfusion rate, duration of chest tube placement, or operative time [72]. It was found, however, that the RATS approach significantly increased both the total and indirect cost compared to VATS [72]. Lastly, RATS led to an increase in lymph node dissected and examination, which also was supported previously in the RATS vs. VATS wedge resection study [71,72]. However, both studies agree that future studies are needed to determine if the increase in lymph node dissection and examination leads to better patient outcomes [71,73].

Lastly, a recent study compared RATS and VATS for early-stage NSCLC via a systematic literature search from 2005 to 2024 [73]. The study produced similar results as the studies mentioned above, especially in regard to lymph node dissection, in which it was found that RATS was significantly better at lymph node dissection when compared to VATS [73]. The studies mentioned previously suggest that RATS is comparable to VATS in most cases, although in some instances RATS is the more robust option, especially in lymph node dissection and examination [71,72,73]. Collectively, these findings highlight the need for larger longitudinal RCTs in order to determine the true clinical benefits of RATS over VATS.

6. Multimodal Approaches and Personalized Medicine

6.1. Integration of Surgery and Immunotherapy

Surgery has been proven to be the standard of care for many cancers, but it is not without its drawbacks. A major issue with surgery is the immunosuppressive effect both pre- and post-surgery. Before the operation, 60–80% of individuals experienced preoperative anxiety [78], causing an increase in sympathetic nerve stimulation, stress-related hormones such as catecholamines and prostaglandins, and behavioral adaptions which may be detrimental to immune health, such as altered sleep or increased alcohol consumption [79]. In particular, the effects of catecholamines and prostaglandins are potent in immunosuppression, downregulating effector T-cells and natural killer (NK) cells while upregulating M2 macrophages, regulatory T-cells, and myeloid derived suppressor cells [16]. Following surgery, immunosuppression comes in different forms, from local and systemic inflammation, to overactivation of regulatory and repair cells, as well as inhibition of NK cell cytotoxicity [80]. Within the first few hours after surgery, pro-inflammatory factors such as IL-6, IL-8, IL-10, and CCL2 are increased, while IFN-y is decreased. Following this, immune cells such as NK, T, and dendritic cells face impairment in their function. This generally lasts up to 2 weeks after the procedure, although the neutrophil to lymphocyte ratio remained elevated for up to 6 months in a pancreatic adenocarcinoma study [80,81]. Another specific post-surgical mechanism found in lung cancer patients is increased expression of PD-L1 on effector T-cells and NK cells as well as reduced quantity of these cells, potentially related to an increase in caspase-3 [82]. Because of this modulation of the body’s normal immune function, immunotherapy has recently been noted as a possible aid to surgery due to its potential to counteract the immunosuppression normally seen in operations.

A primary concern in the integration of immunotherapy treatments and surgery is safety and potential adverse effects. A 2017 study identified 22 patients receiving perioperative ICIs in melanoma, renal cell carcinoma, and urothelial carcinoma [83]. No major complications arose post-surgery, suggesting that these drugs may be started before and continued throughout the surgical and recovery process. While no lung surgeries were noted in this study, the results seem optimistic for generalization as they were found in carcinomas [83]. Nemeth et al. found that immunotherapy of >5 months preceding surgery had similar outcomes as those treated with chemoradiation, and a 30-day mortality of 0.6% with low morbidity, suggesting that the combination of these two methods is likely beneficial [10]. Current research suggests immunotherapy is generally well tolerated, but ICIs have the capacity to cause systemic inflammation when modulating the immune system and thus require further study to determine if their therapeutic action is greater than the potential side effects [17].

With safety of these drugs in conjunction with surgery determined, the next step would be identifying dosing. It is currently generally accepted that the severity of immunosuppression correlates with the invasiveness of the procedure [84,85], although a 2022 study on NSCLC found no significant difference in immune profile of peripheral blood mononuclear cells based on surgical stress [18]. Further research should be undertaken to clarify this matter, as clinical standards for dosing of immunotherapy drugs will likely change if immunosuppression varies with surgery extent.

The timing of immunotherapy can also play a role in therapeutic outcome. In a mouse study on breast cancer, it was determined that neoadjuvant therapy 3 days before surgery was significantly more effective in eradicating metastasis post resection than adjuvant therapy [86]. Similarly, Liu et al. demonstrated that initiating immunotherapy 4–5 days prior to resection was optimal, with declining efficacy when administered both 10 days and 2 days prior [87]. In contrast, Sandbank et al. recommend utilizing immunostimulatory treatment and stopping 1–3 weeks preoperatively while also adding drugs to inhibit prostaglandin synthesis and adrenergic signaling [16]. Currently it is unclear whether better outcomes are observed with longer applications of immunotherapy before or after surgery; this would be an excellent opportunity for future studies.

Research outcomes specific for lung cancers have shown promise in the integration of immunotherapy and surgery, as seen in Figure 3. In a 2022 phase III trial, Forde et al. found that patients who were treated with nivolumab plus chemotherapy prior to surgery had a median event survival 10 months greater than those who underwent standard chemotherapy in lung cancer [11]. Additionally, a complete pathological response was noted in 24.0% of patients as opposed to 2.2% in the control group [11]. These results are consistent with the findings from O’Brien et al., who found median disease-free survival of 53.6 months versus 42.0 months while comparing pembrolizumab and a placebo [12]. A variety of studies and trials have similarly concluded that ICIs which target sites such as PD-L1 can improve the outcome of NSCLC [13,14]. A phase I-IIIa trial from 2021 found major pathological responses of 24% and 50% in neoadjuvant immunotherapy, with the greater response occurring with two ICIs being used in conjunction [15]. Furthermore, it may be possible to combine ICIs with standard chemotherapy treatment for greater effect, although the ideal combination has not been determined [19].

Figure 3. Shows the overlap between treating NSCLC surgically and with immunotherapy. Created in BioRender, version 1.0.0.5; Science Suite Inc.: Toronto, ON, Canada, 2025. https://BioRender.com/mllhbbc (accessed on 13 October 2025).

While ICIs have plentiful completed research, other forms of immunotherapy have lagged. CAR T cell therapy for example has demonstrated excellent results in hematological malignancies but has limited results in solid malignancies. Limitations to this therapy include cost, the need to identify NSCLC cell antigens that are not expressed by healthy lung cells, and poor infiltration of T-cells into the tumor microenvironment [88]. Tyrosine kinase inhibitors have also seen some success, with a study on previously unresectable NSCLC having pathological downstaging of 74.4% and a 5-year OS of 66% [89]. Many tyrosine kinase inhibitors are in the form of EGFR blockers, with overall response rates ranging from 42.1 to 58%, generally landing near a 50% response rate [90,91,92], although one 2023 study identified a rate of 70.2% [93]. This is an encouraging finding for patients who may have tumors that have not responded well to standard ICIs but are ideal candidates for immunotherapy.

Looking forward, ideal combinations of therapies and identification of which lung procedures will benefit most from immunotherapy have not been determined. Additionally, many of the positive results found for these topics occur in early phase trials, and more data must be collected from phase III/IV trials to determine when immunotherapy is most therapeutically beneficial.

6.2. Role of Clinical Team

The complexity of care in NSCLC requires the expertise of multiple specialists from different fields. The roles on a multidisciplinary team (MDT) for NSCLC include pneumologists, thoracic surgeons, medical oncologists, radiation oncologists, pathologists, radiologists, palliative care physicians, and psychologists, among others. Having a wide range of specialists allows avoidance of unnecessary and repeat procedures, proper assessment and ordering of diagnostic tests, and early implementation of disease management [20].

Having multiple specialists can increase patient outcomes in this disease over the course of treatment. A 2024 retrospective cohort study identified that patients who received care with an MDT in NSCLC had increased pulmonary resection in stage I and II (78.6% vs. 59.69%), greater likelihood of longer survival (HR 0.23, 95% confidence interval 0.09–0.55), and decreased waiting time for bronchoscopy, pathologic report, and surgery scheduling [94]. These results seem to indicate that multidisciplinary teams are effective in speeding the process of treatment along for their patient, which can reduce time for tumor growth. Additionally, the speed of treatment may be responsible for the increased likelihood of longer survival, or better communication among healthcare providers may have reduced adverse events and resulted in higher quality of care. An additional study on lung cancer confirms these findings, with greater 5-year survival rates (33.6% vs. 23.0%) for the MDT and an HR of 0.65, 95% confidence interval 0.54–0.77 [95]. The results for these studies were found in the context of traditional lung cancer treatment and do not account for newer immunotherapy treatments. It can be estimated that the addition of newer drugs with dosages and side effects that have not been definitively clinically determined will further necessitate large teams capable of identifying issues and communicating quickly to solve them.

7. Conclusions

Despite advances in medicine and social awareness of risk factors such as smoking, NSCLC remains the most common cancer in the world. Surgery remains the gold standard for early-stage tumors as well as centrally located advanced lesions due to the effectiveness of the treatment and OS. Surgical advancements such as RATS have revolutionized the invasiveness of procedures, reducing recovery and delivering superior outcomes. With progress in trials of ICIs, perioperative immunotherapy is being utilized for better outcomes alongside surgery, although the specific timing with greatest effect remains unclear. For non-resectable cancers, chemotherapy in conjunction with ICIs or other immunotherapeutic strategies are quickly becoming gold standard treatments due to their proven efficacy and relatively well tolerated nature. Data would suggest that using more than one ICI would be beneficial and further targeting with more specific therapies such as bsABs or reactivation of the immune system via CAR-T or virus therapy is useful in resistant tumors. Even when there is low expression of standard ICI targets such as PD-1/PD-L1 and CTLA-4, positive outcomes may be seen utilizing tyrosine kinase inhibitors and CAR-T cell therapy, although both need further extensive studies. CtDNA also provides an exciting alternative to low-dose chest CTs in detection of NSCLC, being faster and cheaper, although sensitivity remains considerably lower, stopping this method from being the standard for detection. Current obstacles to the integration of these methods include a lack of clarity on the ideal administration time of the drugs, uncertainty in which mixes of immunotherapeutic methods work best together, and resistance to ICIs. When these problems are solved, the combination of immunotherapy and surgery has the potential to become the new gold standard of treatment for NSCLC.