Anti-tumor immunotherapy, radiotherapy, and chemotherapy multimodal combination strategies and interactions in unresectable, locally advanced lung cancer: Clinical practice, mechanism, and biomarker research

Immunotherapy has fundamentally transformed the management of lung cancer. For unresectable, locally advanced non-small cell lung cancer (LA-NSCLC) and limited-stage small-cell lung cancer (LS-SCLC), the current standard of care is platinum-based concurrent chemoradiotherapy (cCRT) followed by consolidation immune-checkpoint blockade, a sequence that significantly prolongs progression-free and overall survival. Attempts to deliver immunotherapy concurrently with cCRT have not improved efficacy in randomized trials and have raised additional safety concerns. Induction chemotherapy plus immunotherapy followed by cCRT is biologically rational and feasible, but definitive benefit awaits phase III confirmation. Optimal sequencing, the most effective immunotherapeutic agents, and the best radiotherapy schedules remain active research priorities. The biological rationale for combining radiotherapy and chemotherapy with immunotherapy rests on their capacity to increase tumor immunogenicity, such as by releasing neoantigens, enhancing major histocompatibility complex-I (MHC-I) expression, and promoting dendritic-cell activation, thereby amplifying subsequent T-cell–mediated cytotoxicity. Yet the same cytotoxic stimuli concurrently elicit lymphodepletion, expand regulatory T cells, and trigger pro- inflammatory cytokine cascades that can blunt antitumor immunity. Consequently, the net therapeutic benefit depends on meticulous optimization of sequencing, fractionation, and dosing to harness immunostimulatory efects while minimizing immunosuppressive sequelae. Circulating tumor DNA, metabolic imaging parameters, and real-time immune-profiling are being integrated into non-invasive biomarker platforms that track response and guide post-concurrent chemoradiotherapy (cCRT) immunotherapy decisions. The next generation of curative-intent therapy will be defined by multidisciplinary, patient-centred treatment plans that combine advanced radiotherapy techniques to reduce toxicity, novel agents such as bispecific antibodies or antibody–drug conjugates, biomarker-driven precision medicine, and proactive adverse-event management.