This review summarizes immune resistance in NSCLC through a framework that distinguishes primary resistance from acquired resistance, and discusses mechanism-based biomarkers, translational correlates, and rational therapeutic strategies for overcoming resistance.
Abstract
Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer incidence and mortality worldwide. In recent years, immune checkpoint inhibitors (ICIs), particularly those targeting the programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) axis, have significantly improved survival outcomes in a subset of patients. However, the magnitude and durability of clinical benefit vary considerably according to PD-L1 expression, treatment setting, histological subtype, oncogenic driver status, and whether ICIs are administered as monotherapy or in combination regimens. A substantial proportion of patients therefore exhibit either primary resistance or acquired resistance after an initial response. This review systematically summarizes the key mechanisms underlying immune resistance in lung cancer. These include defects in antigen presentation, such as abnormalities in major histocompatibility complex class I (MHC-I), transporter associated with antigen processing 2 (TAP2), and β2-microglobulin (B2M), as well as dysregulation of the interferon-γ/Janus kinase-signal transducer and activator of transcription (IFN-γ/JAK-STAT) signaling pathway. Tumors frequently exhibit an immune-excluded or ‘cold’ phenotype, which further limits immune recognition and reduces responsiveness to immunotherapy. This review summarizes immune resistance in NSCLC through a framework that distinguishes primary resistance from acquired resistance. Primary resistance reflects failure of immune activation at treatment initiation, usually due to pre-existing tumor-intrinsic or microenvironmental barriers, including impaired antigen presentation, defective IFN-γ/JAK-STAT signaling, low tumor immunogenicity, immune-cold or immune-excluded phenotypes, and suppressive TME states. In contrast, acquired resistance reflects adaptive tumor and immune ecosystem evolution under therapeutic pressure, leading to neoantigen loss, HLA or B2M alterations, compensatory checkpoint activation, progressive T cell exhaustion, TME remodeling, and epigenetic stabilization of immune escape. We further discuss mechanism-based biomarkers, translational correlates, and rational therapeutic strategies for overcoming resistance.
Epidermal growth factor receptor (EGFR) activating mutations are pivotal driver alterations in non-small cell lung cancer (NSCLC), with a markedly higher prevalence in Asian populations, female patients, and never-smokers relative to other subgroups. EGFR tyrosine kinase inhibitors (TKIs) have been established as the first-line standard-of-care therapy for EGFR-mutant NSCLC. The third-generation agent osimertinib significantly improves survival outcomes, with a confirmed median progression-free survival (PFS) of 18.9 months in the first-line setting based on the FLAURA pivotal trial. Nevertheless, acquired resistance universally develops within a finite treatment period, and primary resistance occurs in a subset of patients, collectively constituting the major clinical bottleneck limiting durable therapeutic benefits. EGFR-TKI resistance is characterized by substantial complexity and inter- and intra-tumoral heterogeneity, driven by a spectrum of genetic and non-genetic adaptive mechanisms. Notably, distinct resistance mechanisms differ substantially in clinical actionability, defined as the feasibility of clinical detection, availability of targeted therapeutic options, and potential for clinical translation. Existing review studies mainly categorize EGFR-TKI resistance based on genetic mutation types but fail to integrate clinical practicality, resulting in ambiguous hierarchical logic and limited clinical guiding value. To address this gap, the present review systematically reorganizes and classifies EGFR-TKI resistance mechanisms strictly based on clinical actionability and intervention feasibility, constructing a standardized three-tier hierarchical framework: clinically actionable core resistance mechanisms with mature clinical intervention regimens, potentially actionable auxiliary mechanisms with preclinical evidence but limited clinical validation, and refractory primary resistance mechanisms without routine effective intervention strategies. Specifically, core actionable mechanisms include EGFR on-target secondary mutations and compensatory bypass pathway activation, which are well-validated in clinical cohorts and correspond to mature targeted therapies; potentially actionable mechanisms cover tumor phenotypic transformation, metabolic reprogramming, epigenetic modification, autophagy dysregulation, and tumor microenvironment abnormalities, all of which are supported by robust preclinical data but lack large-scale prospective clinical verification; refractory primary resistance is attributed to inherent tumor genetic backgrounds and host individual factors that currently cannot be effectively targeted in routine clinical practice. On the basis of this hierarchical classification, we further correlate each tier of resistance mechanisms with corresponding targeted therapeutic strategies, including next-generation EGFR-TKIs, pathway-specific combination targeted therapy, novel translational therapeutics, metabolic intervention, and traditional Chinese medicine (TCM)-derived natural product adjuvant therapy. This study aims to clarify the hierarchical logical relationship of heterogeneous EGFR-TKI resistance mechanisms, provide evidence-based references for individualized post-resistance clinical decision-making, and offer feasible directions for subsequent translational research and therapeutic optimization.
Yujia Zhai, Xilong Zhou, Weiming Zhao et al.· American Journal of Cancer R...· 0 citations
Immune checkpoint inhibitors (ICIs), particularly antibodies targeting PD-1/PD-L1 and CTLA-4, have reshaped the treatment landscape of lung cancers, most notably non-small cell lung cancer (NSCLC). Nevertheless, only a subset of patients achieve durable benefit due to primary and acquired resistance that arises from tumor-intrinsic factors (e.g., oncogenic drivers and adaptive signaling), tumor-extrinsic determinants in the tumor microenvironment (TME) (e.g., impaired T-cell infiltration and immunosuppressive myeloid populations), and the dynamic evolution of biomarkers. Accordingly, current clinical and translational efforts in lung cancer focus on rational combination strategies—ICIs with chemotherapy, radiotherapy, and targeted agents (including RTK- and KRAS-pathway inhibitors)—as well as alternative approaches that modulate antigen presentation, myeloid regulation, and cancer stemness. In this review, we define a lung cancer–centered scope and summarize (i) established and emerging ICI-based regimens in lung cancer, (ii) mechanisms of resistance relevant to NSCLC and SCLC, (iii) biomarker integration for patient selection and monitoring, and (iv) future directions to optimize efficacy and safety through combinatory and alternative immunotherapeutic strategies.
Junyoung Park, Choong‐Hwan Kwak, Yu-Chan Chang et al.· Frontiers in Immunology· 0 citations
Small cell lung cancer (SCLC) is an aggressive malignancy with limited treatment options, and the integration of immune checkpoint inhibitors (ICIs) into treatment regimens has reshaped the therapeutic landscape. However, challenges such as rapid resistance and lack of effective predictive biomarkers remain. This review highlights the pivotal roles of biomarkers in SCLC, underscoring their contributions to treatment resistance across tumor-intrinsic mechanisms, immune landscape of the tumor microenvironment (TME) and systemic host factors. Tumor-intrinsic features, including molecular subtypes, genetic alterations such as TP53 and RB1 mutations, and tumor mutation burden (TMB), have shown varying associations with ICI efficacy. Notably, the SCLC-I (inflamed) molecular subtype appears more responsive to immunotherapy. Within the TME, programmed cell death ligand 1 expression, tumor-infiltrating lymphocytes (TILs), regulatory T cells, myeloid-derived suppressor cells, and tissue-associated cytokines and chemokines contribute to immune modulation. High CD8+ TILs are linked to better outcomes, while increased immunosuppressive populations often suppress anti-tumor response. Systemic factors, encompassing both tumor-derived (ctDNA, CTCs, tumor-derived EVs) and host-derived (circulating immune cell phenotypes, MHC expression, immune profile, baseline clinical characteristics) components, provide valuable insights into treatment response and prognosis. Further research is needed to validate biomarkers and investigate combination approaches to overcome resistance, offering hope for improved patient outcomes in SCLC.
Shuxing Wang, Xin-rui Zhao, Yue-yue Zeng et al.· Critical reviews in oncology...· 0 citations
Current evidence supports PD-L1 as the most widely implemented biomarker, but no single factor adequately captures the biological and temporal heterogeneity of treatment response, so integrated, dynamic, and context-specific biomarker models are required to improve precision immuno-oncology.
Longhua Lu, Ze-Yang Zeng, Zi-Qi Guan et al.· Journal of Clinical Question· 0 citations
Background: Lung cancer remains the leading cause of cancer-related mortality, with non-small cell lung cancer (NSCLC) accounting for approximately 85% of cases. Over the past decade, immune checkpoint inhibitors have become a core component of first-line treatment for advanced-stage NSCLC lacking driver mutations. Programmed death-ligand 1 (PD-L1) expression is currently used as the standard biomarker, yet its predictive value remains limited, and in most immunotherapy trials, treatment efficacy has been observed independently of PD-L1 expression status. Enhancer of zeste homolog 2 (EZH2), an epigenetic regulator, promotes immune escape by suppressing antigen presentation and impairing CD8+ T-cell function, thereby generating an immune-cold tumor microenvironment, positioning it as a promising candidate biomarker. Methods: We retrospectively analyzed 102 NSCLC patients treated with immunotherapy at a single center between 2018 and 2024. EZH2 expression was assessed by immunohistochemistry. A cohort-derived 25% threshold was used for the primary exploratory analysis, and the analyses were repeated using a 50% threshold as a sensitivity analysis. Patients were classified as EZH2-high (45.1%) and EZH2-low (54.9%) at the 25% threshold. Results: At the 25% threshold, objective response rate (ORR) was 53.6% in the EZH2-low group and 45.7% in the EZH2-high group (Fisher’s exact p = 0.551), while disease control rate (DCR) was 64.3% and 60.9%, respectively (p = 0.837). Median overall survival (OS) was 37 versus 27 months (log-rank p = 0.323), and median progression-free survival (PFS) was 15 versus 12 months (p = 0.387). No significant correlation was found between EZH2 and PD-L1 expression (r = 0.167, p = 0.138). In treatment-line-adjusted Cox models, EZH2 expression was not associated with OS (hazard ratio (HR) 0.953, 95% confidence interval (CI) 0.533–1.704; p = 0.870) or PFS (HR 0.996, 95% CI 0.573–1.733; p = 0.989), whereas squamous histology was an independent predictor of survival. Results remained non-significant at the 50% threshold. Early progression was uncommon and did not differ significantly by EZH2 status overall or within PD-L1 strata. Conclusions: In this real-world cohort, EZH2 expression was not independently associated with response, early progression, OS, or PFS, and showed no correlation with PD-L1. These exploratory findings do not support the clinical use of EZH2 as a biomarker at this stage; prospective, multicenter studies using predefined thresholds and standardized immunohistochemical methods are needed to clarify its potential role as a marker complementary to PD-L1.
E. Asarkaya, Hatice Asoglu, Abdurrahman Aykut et al.· Journal of Clinical Medicine· 0 citations
Background: The sequential use of anti-programmed cell death (ligand)-1 [PD-(L)1] immune-checkpoint inhibitors (ICIs) followed by targeted tyrosine-kinase inhibitors (TKIs) for advanced non-small cell lung cancer (NSCLC) with oncogenic alterations raises questions about tolerance and efficacy. Recent study results suggested an increased risk of adverse events (AEs) with this sequence. Methods: Multicenter retrospective study on advanced NSCLC patients treated with ICIs followed by targeted therapies between 2015 and 2021. The primary endpoint was the rate of grade 3–5 adverse events (AEs). Main secondary endpoints were progression-free survival (PFS), time-to-treatment failure and overall survival (OS). Results: The analysis included 109 patients (most with EGFR, 30.3%; BRAF, 17.4%; MET exon-14, 17.4%; ALK, 10.1%; and RET, 6.4% gene alterations); 28/109, which is 25.7% of the patients, experienced grade 3/4 AEs and 4/109 (3.7%) experienced grade 5 AEs, leading to the definitive cessation of targeted therapy treatment in 14/32 (44%) of cases; higher grade 3–5 rates were observed with the dabrafenib–trametinib combination (12/16, 75%), capmatinib (4/8, 50%) and crizotinib (8/16, 50%). A last ICI-administration-to-targeted therapy-start interval of <90 days appeared to be associated with grade ≥ 3 AEs (32/82, 39% vs. 0/27 p = 0.001). In these sequential strategies, effectiveness of targeted therapies, in this second-line or later setting, appears to be lower than that in the published historical data. Conclusion: According to this analysis, sequential ICI–targeted therapy use for advanced NSCLC appeared to be associated with more grade 3–5 AEs.
Thomas Pierret, J. Auliac, C. Ricordel et al.· Current Oncology· 0 citations
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