CD49a⁺ NK cells promote M2 polarization and are associated with poor pathological response in NSCLC

Natural killer (NK) cells are key for tumor immune defense. Tissue-resident NK subsets often differ from classical CD16⁺ NKs and can be immunosuppressive. The exact traits and mechanisms of these tissue-resident NKs in the tumor microenvironment (TME) of non-small cell lung cancer (NSCLC) are still unclear. This study aimed to comprehensively analyze NK cells in the NSCLC tumor microenvironment to identify distinct tissue-resident subsets, assess their clinical relevance, and investigate their functional properties and underlying mechanisms in shaping immunosuppression. We identified CD49a⁺ NK cells as a distinct tissue-resident subset in non-small cell lung cancer surgical specimens. Single-cell RNA sequencing revealed that this subset is associated with poor pathological response to neoadjuvant therapy. The abundance of CD49a⁺ NK cells negatively correlates with the formation of tertiary lymphoid structures (TLS). These cells exhibit an altered phenotype, characterized by upregulated immune checkpoint genes, downregulated cytotoxicity-related genes, and uniquely elevated expression of CSF-1. This CD49a⁺ NK cell subset is functionally linked to driving M2 macrophage polarization, and M2 polarization tends to inversely correlate with TLS density. Our findings indicate that CD49a⁺ NK cells contribute to the induction of M2 macrophage differentiation within the tumor stroma and are unfavorable for TLS formation. Our findings identify a specific CD49a⁺ tissue-resident NK cell subset that fosters an immunosuppressive microenvironment in NSCLC by impairing TLS formation and driving M2 macrophage polarization, a mechanism that likely contributes to adverse responses to neoadjuvant therapy.