Disulfidptosis induced by intermittent fasting and metformin enhances the efficacy of anti-PD-1 therapy in renal cancer

Abstract PBRM1-mutant ccRCC is a subtype of ccRCC with limited treatment options. Currently, there were no effective drugs specifically targeting this mutation. Here, we discovered that PBRM1-mutant ccRCC patients with comorbid type 2 diabetes mellitus (T2DM) show significantly prolonged OS and PFS. We further investigated the antitumor effects and mechanisms of metformin using mouse models and cell models. In vivo, the combination of intermittent fasting and metformin significantly inhibits tumor growth and in vitro, glucose deprivation combined with metformin treatment induces marked cell death in PBRM1 KO cells. Microscopic observation revealed this cell death is primarily characterized by cytoskeletal contraction and vesicle formation. Only the disulfidptosis inhibitor, 2-methoxyestradiol (2ME) significantly alleviated the cytotoxicity induced by glucose deprivation and metformin. Disulfidptosis was a novel cell death modality primarily mediated by SLC7A11 upregulation and SLC7A11 was also significantly upregulated in PBRM1-mutant ccRCC cells, further supporting that glucose deprivation combined with metformin activates disulfidptosis. Subsequent RNA-seq and in vitro experiments confirmed that disulfidptosis in ccRCC is immunogenic cell death.The released factors from dying cells potently activated T cell-mediated antitumor activity. Furthermore, intermittent fasting combined with metformin enhanced the therapeutic efficacy of anti-PD1 treatment, providing a promising strategy for personalized therapy of PBRM1-mutant ccRCC.