Smad7 is a negative regulator of immunogenic cell death in colorectal cancer

Induction of endoplasmic reticulum (ER) stress is followed by exposure of calreticulin (CRT) on the cancer cell plasma membrane and elicits an anticancer immune response, referred to as immunogenic cell death (ICD). Smad7 is highly expressed by colorectal cancer (CRC) cells, and its knockdown with a specific antisense oligonucleotide (AS) induces ER stress. We hypothesized that, by preventing ER stress, high Smad7 in CRC cells can contribute to limiting ICD. This study aimed to investigate whether targeted inhibition of Smad7 in CRC cells promotes an anti-cancer immune response. Downregulation of Smad7 in the human HCT116 and DLD1 cells and murine CT26 cells promoted calreticulin translocation to the plasma membrane and this phenomenon was prevented by Tauro-urso-deoxycholic acid, an inhibitor of ER stress. Smad7-deficient cells secreted high levels of ATP and HMGB1, thereby promoting the activation of co-cultured dendritic cells. Mice engrafted with Smad7-deficient CT26 cells developed fewer and smaller tumors than wild-type CT26 cell-engrafted mice and exhibited a marked tumor infiltration with CD8⁺ cells and to a lesser extent CD4⁺ cells. Depletion of CD8⁺ T cells abrogated the inhibitory effect of Smad7 knockdown on the tumor volume. Finally, we showed that, in a vaccination model, implanted Smad7-deficient CT26 cells protected mice from the development of tumors induced by wild-type CT26 cells. These data show that Smad7 deficiency triggers ICD in CRC cells, thus reducing tumor development and growth, and suggest that Smad7 inhibitors could be developed as novel ICD inducers, providing a new concept for antitumor immunotherapy.