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Review

Cancer Resistance to Immunotherapy

by
Rita Khoury
*,†,
Annoir Shayya
*,†,
Cendrella Bou Orm
,
Osama Zein Deen
and
Hady Ghanem
Division of Hematology/Oncology, Lebanese American University Medical Center-Rizk Hospital, Beirut P.O. Box 11-3288, Lebanon
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Immuno 2025, 5(3), 32; https://doi.org/10.3390/immuno5030032
Submission received: 29 April 2025 / Revised: 15 July 2025 / Accepted: 31 July 2025 / Published: 5 August 2025
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Abstract

Immunotherapy has revolutionized cancer treatment. Despite its success across various malignancies, a significant proportion of patients either fail to respond (primary resistance) or relapse after an initial response (acquired resistance). This review explores the different mechanisms underlying resistance to immunotherapy, including tumor-intrinsic factors such as loss of antigen presentation, genetic, and epigenetic mutations. It also examines tumor-extrinsic contributors, such as immunosuppressive cells in the tumor microenvironment, checkpoint molecule upregulation, and microbiome influences. A comprehensive understanding of resistance mechanisms is essential for improving patient selection, developing combination therapies, and ultimately enhancing the efficacy and durability of immunotherapeutic interventions.

1. Introduction

The advent of immune checkpoint inhibitors (ICIs) has significantly transformed the landscape of cancer therapy in recent decades. This is clear through several complex mechanisms whereby our immune response is regulated to better recognize and modify tumor cells or their background. By disabling T cells’ inhibitory brakes and resulting in robust immune system activation and potent anticancer immunological responses, ICIs have revolutionized cancer treatment. This commands an interplay between the innate and adaptive immune cells. This includes but is not limited to the different T cells, dendritic cells, natural killer cells, macrophages, and myeloid-derived suppressor cells. In addition to being the backbone of ICI therapy, T cells also activate other innate and adaptive immune cells to create a strong defense against cancer. Three different ICI classes have been approved for use in humans by the US Food and Drug Administration (FDA): inhibitors targeting cytotoxic T lymphocyte associated antigen 4 (CTLA-4), programmed death 1/programmed death-ligand 1 (PD1/PDL-A), and lymphocyte activation gene 3 (LAG-3). Ipilimumab was the first approved anti CTLA-4 therapy for the treatment of metastatic melanoma. This was based on a pivotal phase III study published in 2010, showing the marked overall survival given the very challenging nature of the disease [1]. Nivolumab and pembrolizumab belong to the second class of ICIs that block programmed cell death protein 1 (PD-1). Atezolizumab, durvalumab, and avelumab are anti PD-L1 medications and are primarily used in the treatment of urothelial carcinoma, Merkel cell carcinoma, and non-small cell lung cancer (NSCLC). Due to their superior clinical efficacy and tolerability as compared to cytotoxic T lymphocyte antigen 4 (CTLA-4) antibodies, these antibodies are increasingly used in clinical settings [2].
A notable change in cancer treatment has occurred due to the extraordinary durability of responses to ICIs. Even after treatment cessation, durable responses were observed as was noted in the pooled analysis of patients with previously treated none-small cell lung cancer when compared to chemotherapy in later lines [3]. Moreover, in the five-year follow-up analysis of metastatic melanoma in both the CheckMate 066, and KEYNOTE-001/006, among complete responders, 88% remained alive at five years, many of which were off treatment [4]. However, some patients do not respond to ICIs or lose their response over the treatment period, therefore raising the importance of understanding the mechanisms of resistance. Resistance to ICIs can be categorized into two main types: (1) primary resistance, which occurs when patients do not respond to ICIs at all; (2) acquired resistance, which occurs when patients initially respond to ICI therapy but later experience disease progression either clinically or radiologically [5].
In this paper, we will review the pharmacology and mechanism of action of FDA-approved ICIs, as well as the pathways leading to both primary and acquired resistance to these treatments focusing on the primary resistance versus the acquired resistance mechanisms. Primary resistance occurs when tumors fail to respond to therapy from the outset using certain pathways that will be detailed below, often due to inherent genetic or molecular characteristics, whereas the acquired resistance emerges after initial clinical response mostly due to adaptation mechanisms or certain down regulation machineries.

2. Immune Checkpoint Inhibitor, Types, and Mechanism of Action

The emergence of ICIs has revolutionized the therapeutic landscape across a broader spectrum of malignancies. Immune checkpoint blockade, initially targeting CTLA-4, and subsequently PD-1 and its ligand PD-L1, and more recently the lymphocyte activation gene LAG-3 has demonstrated durable clinical responses and significant survival benefits. These therapies work by unleashing endogenous antitumor T cell responses that are otherwise suppressed by tumor-mediated immune evasion mechanisms [6].
Selecting the most appropriate immunotherapeutic strategy requires a comprehensive understanding of the three phases of cancer immunoediting—elimination, equilibrium, and escape—as well as the key molecular pathways that govern these processes. Effective antitumor immunity relies on several critical prerequisites: efficient priming and activation of tumor-specific T cells, successful recruitment and infiltration of these effector cells into the tumor microenvironment, sustained immure activity within the tumor tissue, and the maintenance of pro-inflammatory, immune-permissive tumor microenvironment [7].

2.1. CTLA-4

CTLA-4 is an inhibitory receptor primarily expressed on activated T cells and regulatory T cells (Tregs). Its expression is upregulated following T cell receptor (TCR) stimulation. For a naïve T cell to become fully activated, it requires not only TCR engagement with peptide–MHC complexes but also a co-stimulatory signal, principally mediated through CD28 binding to B7 ligands (CD80/B7.1 and CD86/B7.2) expressed on activated antigen-presenting cells (APCs) [2,6]. CTLA-4 competes with CD28 for B7 binding with higher affinity, thereby attenuating co-stimulatory signaling and dampening T cell activation. In preclinical models, blockade of CTLA-4 was shown to enhance antitumor immune responses (Figure 1). In a landmark study, mouse models of colon carcinoma (CT26) and fibrosarcoma (Meth A) treated with anti-CTLA-4 monoclonal antibodies exhibited tumor regression and prolonged survival, demonstrating that CTLA-4 blockade could unleash endogenous T cell-mediated immunity against tumors [8] CD28, competitively inhibiting co-stimulatory signaling [9]. This leads to reduced T cell activation and promotes return to a resting state. CTLA-4 mediates inhibition via 1. intrinsic mechanisms: recruitment of phosphatases, suppression of key transcription factors (NF-κB, NFAT, AP-1), and activation of ubiquitin ligases; and 2. extrinsic mechanisms: competitive binding to B7 ligands, thereby limiting CD28-mediated co-stimulation [9,10,11,12].
In Tregs, CTLA-4 plays a pivotal role in suppressive function and lineage stability; this is evident by a complex pathway that ultimately leads to enzyme ubiquitination of target molecules leading to this suppression [13]. This was also indirectly shown via a study examining knock-out genes in mice rendering them CTLA-4-deficient. This deficiency leads to systemic immune activation, tissue infiltration, and early mortality, proving its role in immune modulation [14]. Given its immunosuppressive role, CTLA-4 blockade has been harnessed in cancer immunotherapy to enhance T cell activation and tumor clearance.

2.2. PD-1 and PD-L1

PD-1, first described in 1992, is expressed particularly on exhausted T cells during chronic antigen exposure, such as in cancer or viral infections. Upon ligand binding (PD-L1 or PD-L2), PD-1 becomes phosphorylated at its ITSM (Immunoreceptor Tyrosine-based Switch Motif) domain. This leads to recruitment of SHP-2 phosphatase, which dephosphorylates key proximal signaling molecules downstream of the TCR in T cells: ZAP70 and CD3ζ, and in B cells: Syk and PI3K [15,16,17].
This dephosphorylation cascade dampens T cell proliferation, cytokine production, and survival by inhibiting the Ras/MEK/ERK and PI3K/Akt pathways [18]. PD-1 signaling functions as a key negative regulator of adaptive immunity. In the context of cancer, PD-L1 is frequently overexpressed on tumor cells, enabling them to engage PD-1 receptors on cytotoxic T lymphocytes. This interaction transmits an inhibitory signal that suppresses T cell effector function, thereby promoting immune evasion and allowing for uncontrolled tumor proliferation. Figure 2. depicts Immune checkpoint pathways and the principles of their targeted blockade.
Therapeutic blockade of the PD-1/PD-L1 axis using monoclonal antibodies reactivates T cell cytotoxicity, enhances tumor antigen recognition, and facilitates immune-mediated tumor cell destruction, leading to meaningful clinical responses across a broad range of malignancies. In a foundation preclinical study, Iwai et al. (2002) demonstrated that genetic or antibody mediated disruption of PD-L1 signaling in mouse models resulted in enhanced antitumor immunity and tumor rejection, providing critical evidence for the development of PD-1/PD-L1 targeted therapies in human malignancies [19]. Overexpression of PD-L1 and PD-L2 in tumors correlates with poor prognosis, accelerated disease progression, and resistance to conventional therapies. A clinical study of 85 patients with hepatocellular carcinoma found that this overexpression was independently correlated with worse overall survival (OS) and disease-free survival (DFS) [19]. Whereas a meta-analysis published in 2019, including multiple neoplasms showed that a high PD-L2 expression predicted both unfavorable OS and DFS, also correlating it with a higher degree of probability of distant disease and post-surgical complications [20].

2.3. LAG-3

LAG-3 (CD223) plays a regulatory role equivalent to CTLA-4 and PD-L1 that involves suppression of immune cell activation and proliferation as well as modulating cytokine release [21]. It was first identified in 1990 by Triebel et al. as a 498 amino acid transmembrane protein. It is characterized by the presence of four extracellular immunoglobulin-like domains, encoded by the LAG3 gene located on chromosome 12 [22]. These four domains share nearly 20% homology with CD4, allowing it to firmly bind to major histocompatibility complex II (MHC II) on antigen-presenting cells, eventually leading to T cell inhibition [23,24].
There are currently three different categories of anti-LAG-3 directed therapies: monoclonal antibodies, bispecific antibodies, and fusion proteins [21]. However, to date, data suggest that anti-LAG-3 monotherapy may not be optimal and thus combination therapy with anti PD-1 is being studied. The first, and currently only approved LAG-3 directed monoclonal antibody, is relatlimab. It is approved in combination with nivolumab in patients with advanced melanoma based on RELATIVITY-047 trial [25].

3. Primary Resistance to Immunotherapy

It is essential to remember that the establishment of antitumor immunity depends on innate immunological activation and stimulation of naive T cells [26]. This can occur via several pathways highlighted below, namely evasion, T cell exclusion, mutational burden of the tumor, and genetic–epigenetic mutations and microbiome.

3.1. Evasion

Anti-PD therapy’s main mechanism of action involves blocking the PD-1/B7-H1 pathway in the tumor microenvironment with monoclonal antibodies against either PD-1 or B7-H1 [27].
Therefore, a direct resistance mechanism is represented by the TME’s absence of expression of either PD-1 or B7-H1 [28]. Tumors lacking B7-H1, for instance, are less likely to respond well to anti-PD treatment and probably have other immune escape mechanisms. T cell infiltration and B7-H1 (PD-L1) expression are two metrics that can be used to describe the tumor immune microenvironment. Clinically evident cancers exhibit local defective immune responses. This method divides tumors into four categories: type I cancers, which do not have tumor-infiltrating T cells or B7-H1; type II cancers, which have both tumor-infiltrating T cells and B7-H1; type III cancers, which have T cells but not B7-H1; and type IV cancers, which have B7-H1 but not T cells. For instance, T lymphocytes are absent from 57% of NSCLCs (45% are type I and 12% are type IV). However, only 17% of NSCLCs are expected to react to anti-PD therapy because they have both TILs and B7-H1 (type II), whereas 26% of NSCLCs have TILs but lack B7-H1 (type III). Immunosuppressive immune cells and the overexpression of other immune inhibitory molecules, such as PD-1H (VISTA), TIM-3, LAG-3, and Siglec-15, are common immune-mediated resistance mechanisms found in type III cancers. A significant percentage of tumors are not responsive to anti-PD therapy, which can be explained by this straightforward TIME classification system [29,30,31,32].

3.2. T-Cell Exclusion

T cell exclusion from the TME signifies a second primary resistance mechanism. More than half of advanced human malignancies (cold tumors) lack substantial tumor-infiltrating lymphocytes in the TME, suggesting that there are additional barriers preventing T cell invasion [33]. Improving clinical results for anti-PD therapy requires overcoming T cell exclusion and boosting T cell penetration into tumors. In preclinical animal models, blocking a number of cytokines that are increased in the TME, including VEGF and TGF-β, boosts T cell infiltration and improves the effectiveness of anti-PD treatment [34,35,36]. Both tumor cells and stromal cells within the TME have been linked in preclinical and clinical research to T cell exclusion [36]. It has not yet been determined if blocking these pathways in cancer patients may prevent T cells from invading tumors, despite several studies suggesting multiple mechanisms [37,38,39]. In 2017, Chen & Mellman highlighted in a conceptual review with experimental data synthesis from baseline tumor biopsies from melanoma, the difference between “hot” and “cold” tumors. The latter division highlighted the response to immunotherapy based on the antitumor activity depicted by the activation or lack of a T cell response.

3.3. Mutational Burden of the Tumor

The mutational burden of the tumor is another well-known biomarker that indicates response or nonresponse to immune checkpoint inhibitors (ICIs). Higher tumor mutational burdens are substantially correlated with response to both anti-CTLA-4 and anti-PD-1 across many cancer indications [40,41].
These tumors all share a high neoantigen load, which makes the tumor more visible to the immune system and increases the potency of the antitumor T cell response that develops after ICI treatment. This shared characteristic potentiates the tumors’ response to ICIs. Tumors with low mutational burdens, such as prostate and pancreatic cancers, may be expected to respond poorly to ICIs given this contribution of mutational burden to ICI efficacy, and this is in fact the case [42]. One of the most well-known clinical examples of this is being evaluated as a biomarker for response to ICIs in the phase II, multi-cohort, non-randomized KEYNOTE-158. This study retrospectively analyzed tumor mutational burden across several types of tumors and found that the higher the tumor mutational burden, defined as greater than or equal to 10 mutations per mega-base, the better the response is to pembrolizumab.
However, there are several exceptions. Anti-PD-1 and anti-PD-L1 therapies are generally effective in treating metastatic renal cell carcinoma and polyomavirus-positive Merkel cell carcinoma, respectively; both of which show little tumor mutational loads [43,44].

3.4. Genetic–Epigenetic Mutations and Microbiome

Important signaling pathways within the tumor may also be altered, which could lead to primary resistance to checkpoint treatments. In addition to stimulating CD8+ cytotoxic T cell activity and leaning toward a Th1 response, interferon-γ (IFN-γ) is a crucial cytokine for triggering and sustaining a strong antitumor response because it also has anti-proliferative, pro-apoptotic, and induces major histocompatibility complex class I (MHC I) upregulation in tumor cells [45,46].
Tumor-intrinsic mutations that alter signaling in the IFN-γ pathway have been found to confer resistance to ICIs, which is not surprising given the significance of IFN-γ in antitumor immunity. Retrospective identification of tumors containing mutations in genes like JAK1/2 and IFNGR1/2 in patients who did not respond to anti-CTLA-4 or anti-PD-1 suggests that tumor-intrinsic IFN-γ signaling is essential for checkpoint blockade effectiveness [47,48].
Another primary resistance mechanism involves microbiome, which has been extensively studied in mouse models. Importantly, recent clinical data demonstrated that patients treated with immune checkpoint inhibitors (ICIs) who received antibiotics had decreased overall survival and progression-free survival, indicating that the composition of the patient’s microbiota influences both primary resistance and ICI responsiveness. Separately, tumor-intrinsic mechanisms such as mutations in the IFN-γ signaling pathway genes (e.g., JAK1/2) also contribute to resistance to checkpoint blockade [49,50,51].
Finally, the epigenetic characteristics of tumors are a factor in primary resistance. Numerous investigations have revealed that mutations in genes linked to the SWI-SNF chromatin remodeling complex may make human tumors more susceptible to ICIs. Additionally, treatment with an epigenetic modulator has been shown to enhance the antitumor response mediated by ICIs by increasing the production of chemokines that attract CD8+ T cells [52,53,54].
Nevertheless, it is unclear if the tumor cells’ epigenetic makeup or T cell fatigue is a factor in resistance, which leaves significant opportunity for additional research into the ways that epigenetics may contribute to ICI nonresponse [55].

4. Acquired Resistance to Immunotherapy

Obtaining a better understanding of resistance, whether primary or acquired, is crucial for determining the best treatment options for patients. However, our understanding of acquired resistance is still limited.
The denominator of patients with a tumor response has increased and the chances of finding patients who responded for a period and then progressed, termed acquired resistance or secondary resistance, increases. The rates of acquired resistance, in contrast to primary resistance, are not well-characterized across tumor types since they are not frequently reported [56].
Cancer cells are continuously changing to create a network of soluble and cellular components that suppresses and induces many inhibitory systems, enabling immune evasion and accelerating the growth and progression of the tumor [56]. By suppressing the production of neoantigens and antigen presentation molecules like MHC I, they became able to avoid immune recognition [57,58]. Cancer cells emit cytokines (e.g., IL-10) and growth factors (e.g., TGF-β, VEGF) to suppress immunity and promote tumor development and metastasis [59].
On the other hand, they activate immune checkpoints like CTLA-4 and PD-1 through autocrine or paracrine signals. They also recruit and activate immunosuppressive cells like T regulatory cells (Tregs), B regulatory cells (B-regs), tumor-associated macrophages (TAMs), and myeloid-derived suppressor (MDSCs) in the tumor microenvironment. Crosstalk between non-immune cells, such as cancer-associated fibroblasts (CAFs) and tumor cells, can suppress antitumor immune responses and promote cancer growth [60,61].
Several reasons, such as the development of compensatory inhibitory mechanisms that adversely modify the antitumor immune response and result in acquired resistance, restrict the efficiency of these immunotherapies.One of the main elements that promotes this resistance is the TME’s molecular and cellular composition [62,63].
The IFN-γ response pathway is a crucial one. For example, in melanoma, whole-exome sequencing revealed tumor expansion with loss-of-function mutations in JAK1 and JAK2. These relapsed tumors lost sensitivity to IFN-γ, indicating resistance to its cytostatic effects [64].
Figure 3 illustrates a visual depiction of how tumors bypass immune detection, showcasing multiple pathways and cellular interactions involved in immune evasion.

5. Conclusions

Understanding the intricate mechanisms behind both acquired and intrinsic resistance to immunotherapy is essential for cancer treatment. It is still unknown how tissue homeostasis is restored or normalized, even after the essential T cell subsets and dendritic cell or macrophage subsets that respond most directly to immune checkpoint inhibitors have been described. In many ways, we now understand more clearly how ICIs result in long-term remissions; however a lot is missing regarding why they might fail. The recently discovered mechanisms of resistance to immunotherapy have been the main focus of this review. We tried to define treatment resistance pathways by dividing them into several groups such as immunological, microbiome, metabolic, and epigenetics; nevertheless, resistance frequently encompasses a confusing number of these groups.
Future research should focus on novel combination therapies that target several pathways simultaneously. Additionally, enhancing our ability to detect resistance in vivo through advanced biomarkers will pave the way for personalized and effective strategies, optimally improving cancer care.

Author Contributions

Conceptualizatio: R.K.; validation: H.G., writing—original draft preparation: R.K., A.S., writing: all authors, supervision: H.G. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data available in a publicly accessible repository.

Conflicts of Interest

The authors declare no conflict of interest.

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Figure 1. Interactions between the antigen presenting cells (APCs) and the receptors on T cells, the major key players in immune regulation.
Figure 1. Interactions between the antigen presenting cells (APCs) and the receptors on T cells, the major key players in immune regulation.
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Figure 2. Immune checkpoint pathway and its blockade mechanism; anti-PD-L1 antibodies (shown in the middle) block the PD-1/PD-L1 interaction reactivating T cells to kill tumor checks and secrete cytokines like interferon-gamma, a key upregulator of the PD-L1 receptor.
Figure 2. Immune checkpoint pathway and its blockade mechanism; anti-PD-L1 antibodies (shown in the middle) block the PD-1/PD-L1 interaction reactivating T cells to kill tumor checks and secrete cytokines like interferon-gamma, a key upregulator of the PD-L1 receptor.
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Figure 3. Comprehensive visual summary of the mechanisms by which tumors escape the immune surveillance depicting several modalities by which the cells interact. (1) The T cell secretion of interferon-gamma which binds to the interferon-gamma receptor (IFNGR1/IFNGR2) on the tumor and activates the JAK1/JAK2 and thus activates STAT which leads to upregulation of MHC-I and PD-L1. (2) T cell recognizes the tumor through TCR-MHC-I/epitope binding. (3) PD-1 on T cell binds PD-L1, leading to T cell inhibition.
Figure 3. Comprehensive visual summary of the mechanisms by which tumors escape the immune surveillance depicting several modalities by which the cells interact. (1) The T cell secretion of interferon-gamma which binds to the interferon-gamma receptor (IFNGR1/IFNGR2) on the tumor and activates the JAK1/JAK2 and thus activates STAT which leads to upregulation of MHC-I and PD-L1. (2) T cell recognizes the tumor through TCR-MHC-I/epitope binding. (3) PD-1 on T cell binds PD-L1, leading to T cell inhibition.
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Khoury, R.; Shayya, A.; Orm, C.B.; Deen, O.Z.; Ghanem, H. Cancer Resistance to Immunotherapy. Immuno 2025, 5, 32. https://doi.org/10.3390/immuno5030032

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Khoury R, Shayya A, Orm CB, Deen OZ, Ghanem H. Cancer Resistance to Immunotherapy. Immuno. 2025; 5(3):32. https://doi.org/10.3390/immuno5030032

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Khoury, Rita, Annoir Shayya, Cendrella Bou Orm, Osama Zein Deen, and Hady Ghanem. 2025. "Cancer Resistance to Immunotherapy" Immuno 5, no. 3: 32. https://doi.org/10.3390/immuno5030032

APA Style

Khoury, R., Shayya, A., Orm, C. B., Deen, O. Z., & Ghanem, H. (2025). Cancer Resistance to Immunotherapy. Immuno, 5(3), 32. https://doi.org/10.3390/immuno5030032

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