Autophagy orchestrates anti-tumor immunity to enhance chemo-sensitivity by upregulation of TIMP-2 through FBXW2/CEBPB axis in Colorectal Cancer

However, molecular properties determining response to chemotherapy are still elusive. Here, we demonstrated that efficacy of 5-FU and Oxaplatin treatment(5-FU/Oxa) requires tumor-cell intrinsic autophagy, particularly fostering a tumor-suppressive microenvironment with an augmented presence of total and active CD8+ T cell populations.

Inhibition of autophagy significantly reduced intra-tumoral abundance of CD8+T cells, thus impeding the efficacy of 5-FU/Oxa. Autophagy-deficient tumor cells exhibited remarkably less production of TIMP-2, a secreted endogenous MMP2/9 inhibitor, upon exposure to 5-FU/Oxa. Knockout of TIMP-2 in tumor cells mimicked the effect of autophagy inhibition, whereas overexpression of TIMP-2 or co-administration of MMP-2/9 inhibitor in autophagy-defective tumor cells successfully restored the efficacy of 5-FU/Oxa treatment which depended on CD8+T cells.