Breaking the Myeloid-Stromal Axis to Treat Colorectal Cancer

Colorectal cancer (CRC) presents an immunological paradox: while CD8+ T cell infiltration is associated with better outcomes, most microsatellite stable (MSS) CRC cases remain resistant to immune checkpoint blockade (ICB), particularly in patients with liver metastases. This resistance suggests alternative immunosuppressive mechanisms, with myeloid cells—especially macrophages—playing a central role in suppressing anti-tumor immunity. Our research has identified two dominant macrophage programs, SPP1+ and IL-4-activated macrophages, that contribute to immune suppression and tumor progression in both human and murine CRC. Importantly, we found that cancer-associated stromal cells promote the accumulation of IL-4-producing eosinophils via IL-33, reprogramming macrophages into a repair-like phenotype that enhances tumor growth. We also found that GREM1+ cancer-associated fibroblasts (CAFs) drive the SPP1+ macrophage program, reinforcing a pro-tumorigenic feedback loop, potentially through IL-1 signaling. We hypothesize that myeloid- stromal crosstalks in the CRC tumor microenvironment (TME) drives immune suppression, stromal remodeling, and tumor invasiveness. To test this, we will: (1) define how the IL-4-myeloid axis promotes CRC progression; (2) dissect the pathogenic interaction between SPP1+ macrophages and GREM1+ CAFs; and (3) evaluate therapeutic strategies targeting these pathways to improve response to ICB. Using in vivo and ex vivo models, including orthotopic mouse tumors and human CRC tissue slices, we aim to establish the therapeutic potential of blocking IL-4Rα, IL-1R, IL-1RAP, and IL-33 pathways alone and in combination with ICB, to inform clinical trials for patients with oligometastatic CRC and liver metastases. Project Number: 1R01CA308427-01 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Thomas Marron | Institution: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI, NEW YORK, NY | Award Amount: $697,131 | Activity Code: R01 | Study Section: Translational Immuno-oncology Study Section[TIO] View on NIH RePORTER: https://reporter.nih.gov/project-details/11279709