A self-amplifying IL-1β-CCL2 circuit between macrophages and cancer-associated fibroblasts drives colorectal cancer progression.

Authors

Yijin Wang, Weiwen Bao, Jiahang Li, Runze Jiang, Chengyao Jiang, Shenglong Li

Published in

Cancer letters. Pages 218896. Oct 14, 2026. Epub Oct 14, 2026.

Abstract

Reciprocal interactions between immune and stromal cells are increasingly recognized as major determinants of colorectal cancer (CRC) progression. However, the specific macrophage and fibroblast states cooperating to establish and sustain a tumor-promoting microenvironment remains incompletely understood. Here, we identify a self-reinforcing inflammatory circuit linking monocyte-derived IL-1β⁺ macrophages with IL1R1⁺ cancer-associated fibroblasts (CAFs) in CRC. Integrated single-cell transcriptomic analyses of human CRC revealed a marked expansion of IL1B-associated inflammatory macrophages and IL1R1⁺ inflammatory CAFs, with their respective and combined transcriptional signatures associated with adverse clinical outcomes. Pseudotime analysis and Ms4a3 lineage tracing supported a predominantly monocyte-derived origin of IL-1β⁺ macrophages in the tumor microenvironment. Mechanistically, macrophage-derived IL-1β activated IL1R1 signaling in fibroblasts, promoting the acquisition and expansion of an inflammatory CAF state. Myeloid Il1b deletion or fibroblast-lineage Il1r1 deletion disrupted this interaction and suppressed tumor growth in vivo. In turn, IL1R1⁺ CAFs produced abundant CCL2, which recruited CCR2⁺ monocytes and replenished the IL-1β⁺ macrophage population. Fibroblast-lineage Ccl2 deletion, myeloid Ccr2 deletion, and CCL2 rescue experiments established the functional requirement of the CCL2-CCR2 axis for closure of this reciprocal circuit. Acquisition of the IL-1β⁺ inflammatory macrophage program was further supported by coordinated NF-κB and AP-1 activity, with RELA and JUN/FOS contributing to IL1B transcriptional regulation. Finally, therapeutic blockade of either IL-1β or CCL2 disrupted the macrophage-CAF circuit, increased intratumoral CD8⁺ T-cell responses, and enhanced the antitumor efficacy of anti-PD-1 therapy. Collectively, our findings establish the IL-1β-IL1R1-CCL2-CCR2 axis as a self-amplifying immune-stromal circuit that sustains a tumor-promoting and immunosuppressive microenvironment in CRC. By demonstrating that disruption of this circuit restores antitumor immune activity and sensitizes tumors to PD-1 blockade, our study provides a mechanistic and preclinical rationale for targeting IL-1β-CCL2-mediated macrophage-CAF crosstalk as a combination strategy to improve immunotherapy responses in CRC.

PMID:
42874989
Bibliographic data and abstract were imported from PubMed on 15 Oct 2026.

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