Foretinib triggers immunogenic cell death and enhances efficacy of anti-CD47 immunotherapy in colorectal cancer

Abstract

Dual-target c-Met/VEGFR kinase inhibitors have emerged as promising therapeutic agents for cancer therapy, although their underlying antitumor mechanisms remain poorly defined. In this study, we demonstrate that foretinib, a selective c-Met/VEGFR2 inhibitor, triggers immunogenic cell death (ICD) in colorectal cancer (CRC) cells. This process is characterized by the surface exposure of calreticulin (CRT) and extracellular secretion of ATP and high-mobility group box 1 (HMGB1), which subsequently drives the maturation and activation of dendritic cells (DCs). Mechanistically, foretinib activates the p53 signaling pathway, thereby transcriptionally upregulating Death Receptor 5 (DR5), a critical mediator of the extrinsic apoptotic cascade. Furthermore, foretinib remodels the tumor immune microenvironment (TIME) by facilitating DCs maturation and potentiating the infiltration and activation of T cells. Moreover, combined treatment with foretinib and anti-CD47 antibody exerts synergistic antitumor effects. Together, these findings uncover a previously unreported immunomodulatory function of c-Met/VEGFR2 inhibition, demonstrating that foretinib elicits potent anti-CRC efficacy via direct cytotoxicity and immunogenic regulation, and highlighting its considerable clinical therapeutic potential.