Mitochondrial mechanisms underlying spatial immune phenotypes in non‑small cell lung cancer: Implications for ICI response and cold‑to‑hot tumor conversion (Review)

Non‑small cell lung cancer (NSCLC) is characterized by marked spatial immune heterogeneity, commonly manifested as immune‑desert, immune‑excluded and immune‑inflamed phenotypes. These phenotypes are closely associated with variable responses to immune checkpoint inhibitors (ICIs). Emerging evidence suggests that they are shaped not only by canonical immune pathways but also by mitochondrial processes that regulate immune priming, T‑cell trafficking and the maintenance of effector function. The present review summarizes how mitochondrial reactive oxygen species, mitochondrial DNA‑cGAS‑STING signaling, pathways mediated by tricarboxylic acid cycle metabolites, and non‑cell‑autonomous mitochondrial transfer may contribute to the establishment and maintenance of distinct spatial immune phenotypes in NSCLC. It is proposed that insufficient activation of innate immunity and impaired dendritic cell priming are particularly relevant to immune‑desert tumors, whereas chronic oxidative stress may reinforce barriers mediated by cancer‑associated fibroblasts (CAFs), transforming growth factor β, and the extracellular matrix in immune‑excluded tumors. By contrast, immune‑inflamed tumors may represent a state in which pre‑existing immune circuitry remains intact and tumor‑infiltrating lymphocytes retain greater mitochondrial fitness and metabolic resilience. The implications of these mechanisms for ICI sensitivity and cold‑to‑hot tumor conversion strategies were further discussed. Current evidence from human studies remains largely correlative, and prospective, spatially resolved functional studies are needed. Nevertheless, integrating mitochondrial biology with spatial immune architecture within a phenotype‑guided framework may generate testable hypotheses for future biomarker development and combination strategies.