Distinct migratory dendritic cell subsets cooperate to prime tissue-resident memory-like CD8⁺ T cells in mouse tumors

Tumor-infiltrating tissue-resident memory (T_RM)-like CD8⁺ T cells correlate with positive prognosis and better responses to cancer immunotherapy, yet the mechanisms underlying their specification remain ill-understood. Here, we use the KP (Kras^G12D, p53^-/-) mouse model of lung adenocarcinoma to investigate how different dendritic cell (DC) subsets shape tumor-specific CD8⁺ T cell responses. Selective ablation of XCR1⁺ DC1s or IRF4-dependent CD11b⁺ DC2s reveal that DC1s, but not DC2s, are required for the generation of tumor-infiltrating effector and exhausted CD8⁺ T cells. By contrast, both migratory DC1s and migratory DC2s contribute to the specification of CD103⁺CD69⁺ T_RM-like CD8⁺ T cells in tumor-draining lymph nodes. Mechanistically, low peptide/MHC-I density on migratory DC2s favors TGFβ-dependent T_RM differentiation, while high peptide/MHC-I density on DC1s promote proliferative expansion of T_RM-like cells; in addition, IL-12 secreted by DC1s enhances CXCR6 expression. Together, our findings uncover complementary functions of migratory DC subsets in shaping anti-tumor T_RM-like CD8⁺ T cell responses, and also implicate targeting multiple DC subsets for optimizing cancer immunotherapy.