Immune checkpoint inhibitor-based combinatory and alternative strategies for immune treatment of lung cancers

Abstract

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.