RT-ICI therapy induces a distal immunometabolic axis that shapes systemic macrophage polarization and enhances local T cell immunity.

Colorectal cancer (CRC) liver metastases remain refractory to immunotherapy due to a profoundly immunosuppressive tumor microenvironment. Here, we conducted a prospective clinical study enrolling 18 patients with microsatellite-stable CRC liver metastases treated with high-dose radiotherapy (RT) followed by anti–PD-1 immune checkpoint inhibitors (RT–ICI). Integrative analysis of single-cell RNA-sequencing, spatial transcriptomics, and peripheral immune profiling revealed that RT–ICI therapy reprograms both tumor-intrinsic and immune compartments. RT triggered the emergence of an APOA2⁺ tumor cell state characterized by enhanced lipid metabolic activity and transient elevation of circulating HDL. This metabolic reprogramming, in turn, promoted systemic activation of CETP⁺ M2-like macrophages, a population marked by high LXR/RXR transcriptional activity and enriched expression of immunosuppressive and lipid-processing genes. Despite their expansion, CETP⁺ macrophages localized preferentially to non-irradiated tumor regions, suggesting a distal immunometabolic effect driven by HDL-mediated signaling. Concurrently, combination therapy expanded GZMB⁺ effector T cells and induced a novel population of inflammatory–toxic T cells (IT_T), which exhibited high cytotoxicity and spatial co-localization with CXCL10⁺ macrophages. Ligand–receptor analysis and pseudotime modeling revealed that irradiated tumor cells acted as “in situ vaccines” by enhancing MHC–TCR interactions and promoting T cell differentiation along non-exhausted cytotoxic lineages. Together, these findings reveal a dual mechanism by which RT–ICI therapy enhances local anti-tumor immunity while modulating systemic lipid metabolism and macrophage polarization, offering insights for combinatorial immunotherapy design in immunologically “cold” tumors.