Aug 2026· Journal of Clinical Question· 0 citations· 113 references
TL;DR
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.
Abstract
Immune checkpoint inhibitors (ICIs), particularly programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) inhibitors, are central to the treatment of non-small cell lung cancer (NSCLC), and a subset of patients achieves durable benefit. In historical studies of broadly selected patients receiving ICI monotherapy, objective responses occurred in approximately 20%, although response rates vary substantially according to treatment line, PD-L1 expression, molecular subtype, patient selection, and the use of combination regimens. This narrative review used targeted searches of PubMed/MEDLINE, ClinicalTrials.gov, and reference lists of key publications to identify English-language evidence available through May 2026, prioritizing pivotal randomized trials, prospective translational studies, consensus statements, guidelines, and recent high-quality reviews. We critically examine tumor-microenvironmental features, PD-L1 expression, tumor mutational burden (TMB), oncogenic driver alterations, combination strategies, and patient-related factors that may influence PD-(L)1 inhibitor efficacy. Although other immune checkpoints, including cytotoxic T-lymphocyte-associated protein 4 and lymphocyte-activation gene 3, are discussed when directly relevant to combination therapy, the principal focus is PD-1/PD-L1-directed treatment. 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. Integrated, dynamic, and context-specific biomarker models, supported by prospective validation, are therefore required to improve precision immuno-oncology.
The combination of PD-1 inhibitors and chemotherapy may provide a significant OS and PFS benefit relative to PD-L1 inhibitors plus chemotherapy in NSCLC and a similar safety profile.
Cui Dang, Jing-zhang Li, Hong Chen et al.· PeerJ· 0 citations
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.
Bo Yuan, Wenzhi Deng, Juan Luo et al.· Frontiers in Immunology· 0 citations
Limited benefit in other cancer subsets highlights the need for biomarker discovery and optimization of therapeutic strategies, including addition of antibody-drug conjugates to ICIs, next-generation checkpoint modulation, personalized neoantigen vaccines, and engineered cellular immunotherapy.
Victor M. Samperio, Ruba Alchaikh Hassan, Aishwarya Ghonge et al.· Expert Opinion on Biological...· 0 citations
It is found that ICI monotherapy significantly improves overall survival in NSCLC with PD-L1 expression ≥50% compared with platinum-based chemotherapy, and first-line atezolizumab plus chemotherapy extended median overall survival to 12.3 months, compared with 10.3 months in extensive-stage SCLC.
Mojeeb Abdo Abdullah Qasem, T. Budhy, D. Suprabawati et al.· Health Dynamics· 0 citations
A dual-source PD-L1 framework is proposed to discuss the potential contributions of tumor cell-derived and immune cell-derived PD-L1 to GBM-mediated immunosuppression and therapeutic response and a multilayer resistance model involving the blood–brain barrier, an immunologically cold tumor microenvironment, and compensatory immunosuppressive networks is outlined.
Junlin Lu, Xuxin Zhang· Eurasian Journal of Medicine...· 0 citations
