Monocyte-derived macrophages promote intraepithelial infiltration of effector memory CD8 ⁺ T cells in tumors regressing after STING agonist treatment

Despite the clinical success of cancer immunotherapies, the cellular interactions driving tumor regression remain incompletely understood. Here, we investigated the dynamic remodeling of the tumor immune microenvironment during regression of transplanted PyMT mammary tumors following STING agonist treatment. Using scRNA-seq of sorted CD8 ⁺ T cells and myeloid cells, combined with imaging approaches, we identified major changes in both lymphoid and myeloid compartments during tumor regression. Regressing tumors showed a transient accumulation of Ly6C ^hi monocyte populations associated with a decline in macrophage subsets, while effector and memory CD8 ⁺ T-cell populations increased at the expense of exhausted T cells. Interaction analyses predicted enhanced chemotactic and adhesion interactions between CXCL9 ⁺ Ly6C ^hi monocytes and effector CD8 ⁺ T cells. Consistently, dynamic imaging revealed increased CD8 ⁺ T-cell motility and infiltration into tumor cores following treatment. In particular, CXCR6 ⁺ effector CD8 ⁺ T cells transiently accumulated within tumor islets during regression before relocalizing to stromal regions. Together, these findings reveal a coordinated spatiotemporal remodeling of myeloid and CD8 ⁺ T-cell populations during immunotherapy-induced tumor regression and highlight cooperative interactions that may promote durable anti-tumor immunity.