Killer-cell dominance dichotomy governs tumor immune networks and stratifies inflamed cancers
Li, A.-N.; Yu, Z.; Zhang, W.; Chang, H.; Feng, S.; Yang, X.; Xiong, K.; He, L.; Zhao, Z.; Shen, L.; Tan, Z.; Du, W.; Zhong, L.; Zhang, X.; Hu, Y.; Su, X.; Wang, R.; Fu, S.; Zhang, L.; Hong, S.
Show abstract
Cancer immunotherapy benefits remain limited, even among "hot" tumors with high killer lymphocyte infiltration. Here, we investigated the population-level architecture of killer cells based on nearly 5,000 pan-cancer scRNA-seq samples, together with orthogonal validation by spectral cytometry and spatial transcriptomics. Unlike the prevailing "hot-cold" paradigm, which assumes coordinated infiltration of multiple cytotoxic lineages, we uncovered a conserved framework wherein terminal cytotoxic immunity in individuals or malignancies diverges into states dominated by either exhausted CD8+ T cells (Tex) or CD56dimCD16hi NK (NK1) cells. Despite the complexity of the tumor microenvironment, Tex-NK1 divergence governs the primary axis of tumor-intrinsic and tumor-extrinsic variance. Distinct from the conventional view that NK cells positively contribute to immunotherapy efficacy, NK1-skewed tumors, although highly cytolytic, are refractory to current immune checkpoint blockade regimens. This killer divergence defines a foundational axis of cancer immunity and provides a resource for prioritizing next-generation targets for NK-directed immunotherapy.
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