Macrophage states and immunometabolic adaptation in peritoneal metastases from colorectal cancer

Immunotherapy responses in colorectal cancer peritoneal metastases (CRCPM) are not determined by mismatch repair (MMR) status alone. Most MMR-proficient/microsatellite-stable (pMMR/MSS) tumors have low baseline sensitivity, while MMR-deficient/microsatellite instability-high (dMMR/MSI-H) tumors do not respond uniformly, particularly in patients with ascites. This Mini Review compares evidence across compartments and disease stages: human associations, macrophage-resolved functional studies and interventions altering immunotherapy efficacy in mice. Human ascites and tissue studies identify resident-like and monocyte-associated macrophages, including C1Q⁺ and SPP1⁺ states, but shared markers do not establish equivalent functions or origins. During niche conditioning and early seeding, ABCA9-dependent cholesterol handling, tumor-derived lysophosphatidic acid signaling and TLR4-CXCL10 activation can support local T-cell-mediated tumor control, although these studies did not test immune checkpoint blockade (ICB) or adoptive cell therapy (ACT). In established disease, SPP1-associated macrophage-intrinsic peroxisome proliferator-activated receptor-γ (PPARγ) programming and extracellular SPP1-CD44 signaling restrain CD8⁺ T cells, and SPP1 perturbation improves anti-PD-1 and ACT responses in mice. The relative contributions of these routes to treatment rescue remain unresolved. TIM-4 and MerTK provide distinct non-metabolic constraints. Human evidence for the resistance-associated SPP1 state remains cross-sectional. Lipid-related pathways in CRCPM models thus have opposing immune effects rather than acting as a single metabolic switch.