Life Sciences · Oct 17, 2026

Dapagliflozin alleviates CYH33-induced hyperglycemia and preserves antitumor immunity against ovarian cancer in type 1 diabetic mice

By Sun J, Xu L, Qu H et al.

PI3K is frequently hyperactivated in ovarian cancer and has emerged as a promising therapeutic target. CYH33 is a novel PI3Kα-selective inhibitor that has been approved in Japan for the treatment of ovarian clear cell carcinoma harboring PIK3CA mutations. However, its on-target adverse effect of hyperglycemia limits its clinical application, particularly in patients susceptible to diabetes, underscoring the urgent need to optimize therapeutic strategies to improve both safety and efficacy. In this study, we employed an ID8 syngeneic murine ovarian cancer model and demonstrated that CYH33 significantly inhibited tumor growth with a modest effect on glucose homeostasis. We then established mouse models of type 1 (T1D) and type 2 diabetes (T2D) to expose hyperglycemia induced by PI3K inhibition and identified that dapagliflozin effectively alleviated CYH33-induced hyperglycemia while preserving its antitumor activity in T1D mice. Mechanistically, the combination of CYH33 and dapagliflozin may improve the immunosuppressive tumor microenvironment in T1D mice, as evidenced by upregulation gene sets involved in interferon-α and interferon-γ response, as well as significantly enhanced infiltration of CD8⁺ T-cell in ID8 tumors. Furthermore, this combination synergized with anti-PD-1 antibody to further enhance antitumor efficacy. These findings provide a potential strategy for optimizing the clinical use of PI3K inhibitors and shed light on metabolic interventions to modulate tumor immune microenvironment.

doi.org/10.1016/j.lfs.2026.124743PubMed 42892524Interventions