TY  - JOUR
T1  - Macrophage CCL7 Drives Colorectal Cancer Immunotherapy Resistance by Modulating Macrophage and CD8⁺ T Cell Infiltration
A1  - Marco Antonio Bianchi
A1  - Luca Francesco Romano
A1  - Giulia Elena Conti
JF  - Archive of International Journal of Cancer and Allied Science
JO  - Arch Int J Cancer Allied Sci
SN  - 3108-4834
Y1  - 2021
VL  - 1
IS  - 1
DO  - 10.51847/cK3obzkwMW
SP  - 171
EP  - 188
N2  - Although immune checkpoint inhibitors (ICIs) have emerged as a transformative approach in cancer immunotherapy, their clinical benefit in colorectal cancer (CRC) remains modest. Elucidating the mechanisms that underlie resistance to ICIs in CRC is critical for identifying novel therapeutic targets. To dissect the role of CCL7 in CRC, we employed myeloid-specific Ccl7 knockout mice alongside MC38 tumor-bearing models. Tumor tissues were analyzed using proteomics, RNA sequencing, and flow cytometry to examine the impact of CCL7 on the immune landscape within the tumor microenvironment.

Our findings reveal that CRC tumors with high infiltration of CCL7-expressing tumor-associated macrophages (TAMs) exhibit reduced responsiveness to ICIs. Loss of CCL7 in myeloid cells diminished immunosuppressive TAM populations and facilitated the recruitment of activated CD8+ T cells into the tumor. Mechanistic studies demonstrated that CCL7 drives peroxisome formation and fatty acid oxidation in TAMs, reinforcing their immunosuppressive behavior through the PI3K-AKT-PEX3 pathway. Additionally, CCL7 suppresses the AKT2-STAT1-CXCL10 signaling axis, limiting CD8+ T cell infiltration. Therapeutically, CCL7 inhibition delayed tumor growth and synergized with anti-PD-L1 therapy to enhance antitumor effects. This study identifies CCL7+ TAMs as key mediators of ICI resistance in CRC and delineates the molecular circuits involved, supporting CCL7 as a promising combinatorial target to improve immunotherapy outcomes.
UR  - https://smerpub.com/article/macrophage-ccl7-drives-colorectal-cancer-immunotherapy-resistance-by-modulating-macrophage-and-cd8-hpihwhhicdt9fhh
ER  -