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.
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.
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