Macrophage states and immunometabolic adaptation in peritoneal metastases from colorectal cancer

Abstract

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.