CCL7 macrophages are emerging as a key barrier to effective immunotherapy in colorectal cancer (CRC). Immune checkpoint inhibitors (ICIs) have reshaped treatment for a subset of patients, particularly those with microsatellite instability-high or mismatch repair-deficient (MSI-H/dMMR) tumors. Yet even within this immunotherapy-sensitive population, up to half of metastatic patients fail to respond or ultimately relapse. This has shifted attention toward the tumor immune microenvironment (TIME), where myeloid cells—especially tumor-associated macrophages (TAMs)—are increasingly recognized as critical regulators of treatment resistance.
A recent mechanistic study identifies a distinct population of CCL7-expressing TAMs as a central driver of resistance to PD-1/PD-L1 blockade in CRC. Through a combination of human data, mouse models, and multi-omics, the authors show that CCL7 not only fuels tumor growth but also remodels the myeloid compartment and T-cell trafficking in ways that blunt effective antitumor immunity. Importantly, pharmacologic or antibody-mediated CCL7 blockade delays CRC progression and enhances the efficacy of anti–PD-L1 therapy, nominating CCL7 as a promising immunotherapy target.
Title: Macrophage CCL7 promotes resistance to immunotherapy for colorectal cancer by regulating the infiltration of macrophages and CD8+ T cells
Authors: Yijiao Chen, Xudong Liu, Jiongming Chen, Liwen Kuang, Nan Zhang, Danyang Li, Dan Zhao, Dongmei Xue, Juan Lei, Jiangang Zhang, Yongsheng Li1 2 3 4orcid logo, Lei Wu.
Published in Journal for ImmunoTherapy of Cancer, November 2025.
Background
CCL7 (monocyte chemoattractant protein-3) is a well-characterized chemokine known to recruit monocytes and other immune cells to sites of inflammation. In cancer, CCL7 has been linked to proliferation, epithelial–mesenchymal transition, invasion, and metastasis across several tumor types, including CRC. Most prior work, however, has focused on tumor cell–intrinsic signaling, such as activation of JAK–STAT and ERK–JNK pathways downstream of CCL7–receptor interactions.
What remained largely unknown was how CCL7 shapes the TIME—particularly the behavior of TAMs—and whether this contributes to failure of immune checkpoint blockade. The current study was designed to close this gap, with a specific focus on MSI-H/dMMR CRC patients who do not benefit from ICIs.
Study Design: Integrating Human Datasets and Mouse Models
The investigators combined:
- Single-cell RNA sequencing datasets from patients with CRC who were either responsive or non-responsive to ICIs.
- Bulk RNA-seq and clinical outcomes data from larger CRC cohorts.
- Serum and tissue analyses of CCL7 in patients and healthy donors.
- Multiple mouse models, including myeloid cell–specific Ccl7 conditional knockout (Ccl7 MKO) mice, MC38 and CT26 tumor-bearing models, and combination treatment experiments with CCL7 inhibitors and anti–PD-L1 antibodies.
- High-resolution mechanistic tools such as lipidomics, Seahorse metabolic assays, proteomics, RNA-seq of TAMs, and in vitro co-culture systems.
This integrative approach allowed the team to connect clinical resistance patterns with cellular phenotypes and molecular pathways.
CCL7+ TAMs Are Enriched in Non-Responders and Predict Poor Outcomes
Analysis of scRNA-seq data from CRC patients treated with ICIs revealed that tumor-infiltrating myeloid cells in non-responders expressed higher levels of chemokines, including CCL7, compared with responders. CCL7 was particularly enriched in a subset of TAMs rather than in all myeloid cells.
This observation was validated in independent cohorts and tissue analyses. CCL7+ macrophages were more abundant in CRC tumors than in adjacent non-tumor tissue, increased with advancing tumor stage, and were associated with worse survival. Serum CCL7 concentrations were elevated in CRC patients compared with healthy donors, and the proportion of CCL7+ macrophages was higher in both tumor and peripheral blood. In murine MC38 tumors, serum Ccl7 levels positively correlated with tumor volume.
These data together suggest that CCL7+ TAM accumulation is a hallmark of an immunosuppressive, treatment-resistant microenvironment.
CCL7 Orchestrates Macrophage Polarization and T-Cell Suppression
Functionally, myeloid-specific deletion of Ccl7 in mice resulted in smaller tumors across multiple CRC models. In Ccl7 MKO mice, tumors exhibited:
- Increased infiltration of CD8+ T cells, with higher frequencies of IFN-γ–producing cells.
- Decreased infiltration of TAMs, dendritic cells, and myeloid-derived suppressor cells.
- A shift in macrophage polarization toward a more proinflammatory, M1-like phenotype (iNOShigh, Arg1low).
Conversely, recombinant CCL7 treatment promoted tumor growth in vivo. CCL7 exposure pushed macrophages toward an M2-like, immunosuppressive state, characterized by increased Arg1 and Mrc1 and reduced Nos2 and Tnfa, along with lower ROS production. Co-culture experiments showed that CCL7-deficient TAMs were less capable of suppressing CD8+ T-cell proliferation and effector function.
Collectively, these findings position CCL7 as a key driver of immunosuppressive TAM programming, with direct consequences for T-cell activation in CRC.
CCL7–PEX3–Peroxisome Axis Supports TAM Immunosuppression
The study also reveals that CCL7’s effects on macrophages are metabolically mediated. Gene set enrichment analysis and lipidomics indicated that CCL7+ TAMs are enriched for fatty acid metabolism and PPAR signaling, with high levels of fatty acid oxidation (FAO) genes such as ACADVL and PPARG.
CCL7-deficient TAMs had fewer lipid droplets, reduced free fatty acid content, fewer mitochondria, lower oxygen consumption rates, and decreased ATP production. In contrast, CCL7 treatment enhanced lipid accumulation and mitochondrial respiration. Inhibition of FAO via etomoxir shifted macrophages away from an M2-like state toward an M1-like phenotype.
Proteomic and transcriptional profiling identified PEX3, a central peroxisome biogenesis factor, as a key downstream effector. CCL7 upregulated PEX3 and the peroxisome marker PMP70, while Pex3 knockdown reduced FAO, increased ROS, and reversed M2 polarization. These effects were mediated through activation of the PI3K–AKT pathway. Blocking PI3K with BEZ235 abrogated CCL7-driven PEX3 upregulation, peroxisome expansion, and immunosuppressive marker expression.
This defines a CCL7–CCR2–PI3K–AKT–PEX3 axis that links chemokine signaling to metabolic reprogramming and sustained TAM immunosuppression.
Blocking T-Cell Trafficking
Beyond reshaping macrophage metabolism, CCL7 also disrupts T-cell recruitment. Ccl7 knockout TAMs showed increased expression and secretion of CXCL10, a chemokine crucial for CD8+ T-cell trafficking into tumors. Ccl7 MKO mice had higher serum CXCL10 and enhanced migration of CD8+ T cells toward tumor-conditioned media and into tumors in vivo.
Mechanistically, CCL7 suppressed the AKT2–STAT1–CXCL10 axis. Ccl7-deficient TAMs exhibited increased Stat1 and Akt2 expression, whereas CCL7 treatment reduced STAT1. Knockdown of Ccr2, a dominant CCL7 receptor on TAMs, increased STAT1 and AKT2, supporting a model in which CCL7–CCR2 signaling restrains CXCL10 production and thereby limits cytotoxic T-cell recruitment.
Therapeutic Targeting of CCL7 Macrophages
The translational potential of these findings was tested using both CCL7 neutralizing antibodies and the small-molecule inhibitor bindarit. In multiple CRC mouse models, CCL7 blockade:
- Delayed tumor growth and extended survival.
- Reduced TAM infiltration and shifted them toward a more M1-like state.
- Increased intratumoral CD8+ T cells and enhanced IFN-γ and TNF-α production.
Combining anti-CCL7 with anti–PD-L1 therapy produced superior tumor control and survival compared with either monotherapy, with further reductions in TAMs and stronger CD8+ T-cell activation.Correlative analyses of human CRC datasets showed positive associations between CCL7 and CD163, MRC1, and PEX3 expression, reinforcing the clinical relevance of this axis.
Conclution
This work positions CCL7+ TAMs as a mechanistically defined driver of ICI resistance in CRC. By coupling peroxisome-dependent metabolic reprogramming with suppression of CXCL10-mediated T-cell recruitment, CCL7 creates a microenvironment that is both myeloid-dominated and T cell–poor.
Therapeutically, these findings suggest that targeting CCL7—using agents such as bindarit or anti-CCL7 antibodies—could recondition the TIME, restore sensitivity to checkpoint blockade, and offer a rational combinatorial strategy for patients with CRC who fail PD-1/PD-L1 therapy. Further clinical studies will be needed to validate CCL7 as both a biomarker of resistance and a druggable node in immunotherapy-based treatment algorithms.
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