IFITM1 enhances anti-tumor function of unconventional TCRαβ double negative T cells by upregulating mitophagy

Unconventional TCRαβ⁺ CD4^-CD8^- double negative T cells (DNT) can effectively impede the progression of leukemia, lymphoma, and solid tumors, highlighting their potential as a novel and effective cell therapy approach for cancer. However, the intrinsic mechanisms regulating DNT homeostasis and anti-tumor functions remain unclear. In this study, we discovered that DNT highly expressed IFITM1 (interferon-induced transmembrane protein 1) and further demonstrated that IFITM1 actively regulated the anti-tumor function of DNT both in vitro and in vivo. Furthermore, our investigation revealed that IFITM1⁺ DNT exhibited elevated expression of key molecules involved in immune cell-mediated anti-tumor responses, such as perforin, granzyme B, and NKG2D. Overexpression of IFITM1 promoted DNT anti-tumor activity. Notably, IFITM1 regulated mitophagy, which contributed to the improved mitochondrial function in DNT. Mechanistically, IFITM1 in the mitochondria of DNT interacts with the autophagosomal cargo protein p62/SQSTM1, recruiting more p62/SQSTM1 to the mitochondria, thereby promoting mitophagy. It is worth noting that IFITM1 is also highly expressed in activated human DNT (hDNT), and its regulatory effect on DNT mitophagy, homeostasis, and anti-tumor function has been validated. In conclusion, IFITM1 has emerged as a crucial player in enhancing DNT-mediated anti-tumor activity by regulating mitophagy and mitochondrial function. These findings suggested that upregulating IFITM1 expression in DNT may enhance mitophagy and promote DNT survival and cytotoxic functions, ultimately providing better control over cancer.