Immune checkpoint inhibitor resistance in non-small cell lung cancer: An updated view through the cancer-immunity cycle

Despite the transformative impact of immune checkpoint blockade (ICB) in non-small cell lung cancer (NSCLC), durable responses remain limited to a subset of patients. Resistance-either intrinsic or acquired-continues to undermine the full therapeutic potential of immunotherapy. The cancer-immunity cycle provides a useful conceptual scaffold to dissect the multistep requirements for effective antitumor immunity. Recent advances in single-cell technologies, spatial profiling, longitudinal immune monitoring, and real-world clinical datasets have uncovered additional layers of complexity, including non-canonical pathways involving tumor metabolism, stromal architecture, vascular remodeling, epigenetic plasticity, microbiome-immune crosstalk, and host-related determinants of response. In this review, we provide an updated and integrated synthesis of both primary and acquired resistance mechanisms across each phase of the cancer-immunity cycle. We emphasize pathways that have gained mechanistic or clinical relevance in recent NSCLC literature and consolidate them in an updated reference figure (Figure 1). To strengthen translational relevance, we additionally include a dedicated section on host-related determinants of ICI efficacy-including immunosenescence, performance status, comorbidity burden, systemic inflammation, body composition, and concomitant medications-and a stepwise summary of representative primary versus acquired mechanisms with NSCLC clinical anchors (Table 1). Our goal is to frame resistance not as a single lesion, but as a dynamic tumor-host system that must be mapped to inform biomarker development and rational combination strategies.