Evolution of SPP1+ cavity macrophage-mediated immunotherapy resistance in peritoneal metastasis of colorectal cancer

The immunometabolic basis of therapy-resistant colorectal cancer (CRC) peritoneal carcinomatosis with malignant ascites remains poorly defined. Here, we profile ascites immune cells from 20 patients across treatment-naive, chemo/targeted therapy-refractory, and immune checkpoint blockade (ICB)/adoptive T cell therapy (ACT)-resistant CRC. Single-cell RNA sequencing identifies SPP1 + cavity macrophages as drivers of CD8 + T cell dysfunction. Proteomic profiling of 36 patients confirms SPP1 enrichment in ICB/ACT-resistant peritoneal metastases. Mechanistically, SPP1 sustains an M2-like program via PPARγ activation and lipid uptake. SPP1 deficiency reduces PPARγ ligand precursors, triggering NF-κB-driven macrophage reprogramming and reversing CD8 + T cell suppression. Supplementation with 15 d-PGJ 2 and fatty acids restores the M2 phenotype. In vivo , macrophage-specific SPP1 knockout enhances cytotoxic T lymphocyte infiltration and ICB efficacy, while SPP1 neutralization overcomes ICB resistance and augments ACT efficacy. Thus, SPP1 + cavity macrophages are central immunometabolic regulators, and SPP1 inhibition represents a promising strategy to overcome immunotherapy resistance in this lethal disease.