HIF1α promotes tumor chemoresistance via recruiting GDF15-producing TAMs in colorectal cancer

Chemoresistance is a tremendous challenge to efficacy of systemic chemotherapy which is the preferred treatment for the advanced CRC patients. More tumor-associated macrophages (TAMs) are recruited into the CRC tumor under chemotherapy, which are highly implicated in the chemoresistance development, but the underlying molecular mechanism is unclear. Here, we present that activated HIF1 alpha signaling in CRC cells under chemotherapy drives the expression of HMGB1 to promotes macrophage infiltration and in turn chemoresistance development. Chemotherapeutic treatment with 5-FU leads to increased recruitment of macrophages into tumors, which display tumor-protective alternative activation. Mechanistically, tumor HIF1 alpha signaling activated by chemo-induced ROS drives the transcription of HMGB1 to promote more macrophage infiltration into CRC tumor. Furthermore, high levels of GDF15 produced by TAMs impair the chemosensitity of tumor cells via enhancing fatty acids beta-oxidation. Together, our current study reveals a new insight into the cross-talking between tumor cells and immune cells, and provides novel drug targets for clinic treatments for CRC.

Automated summary

Chemoresistance in advanced CRC patients undergoing systemic chemotherapy is associated with increased recruitment of tumor-associated macrophages (TAMs) into the tumor. Activated HIF1 alpha signaling in CRC cells under chemotherapy drives the expression of HMGB1 to promote macrophage infiltration, leading to the development of chemoresistance. TAMs produce GDF15 which impairs the chemosensitivity of tumor cells. These findings provide new insights into potential drug targets for CRC treatment.