Lung cancer stem cells in the tumor microenvironment: translational biomarkers and therapeutic strategies for immune evasion and treatment resistance.

Lung cancer remains the leading cause of cancer-related death worldwide. Although immune checkpoint inhibitors and targeted therapies have improved outcomes, durable benefit is restricted by primary resistance, acquired resistance, minimal residual disease, and relapse. Lung cancer stem cells (LCSCs) represent a plastic, therapy-resistant tumor subpopulation with self-renewal capacity, lineage adaptability, and marked interactions with the tumor immune microenvironment (TIME). In this review, we frame LCSCs and the TIME as a reciprocal regulatory network rather than as independent biological compartments. TIME components, including tumor-associated macrophages, myeloid-derived suppressor cells, regulatory T cells, cancer-associated fibroblasts, hypoxia, and extracellular matrix remodeling, sustain LCSC stemness through paracrine signaling, niche formation, metabolic adaptation, and epigenetic regulation. Conversely, LCSCs remodel the immune ecosystem through PD-L1, B7-H3, CD47, CXCL12/CXCR4, CCL2, IL-6/STAT3, TGF-β, extracellular vesicles, and impaired antigen presentation. This self-reinforcing network promotes immune evasion, suppressive immune-cell recruitment, treatment failure, and recurrence. We further classify LCSC-related markers according to translational use, including identification markers, prognostic markers, immunotherapy-response markers, monitoring biomarkers, and therapeutic targets, while indicating whether available evidence is mainly derived from non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), or both. Finally, we distinguish clinically established immunotherapeutic strategies from investigational LCSC-directed approaches and discuss how single-cell sequencing, spatial transcriptomics, organoids, patient-derived xenografts, and liquid biopsy may support biomarker validation and rational combination therapy.