Targeting mesothelin-CD24 axis repolarizes tumor-associated macrophages to potentiate PD-1 blockade therapy in high-grade serous ovarian cancer

Background High-grade serous ovarian cancer (HGSOC) is a highly aggressive malignancy marked by an immunosuppressive tumor microenvironment that hinders effective immune responses. A key feature of this environment is the extensive infiltration of myeloid cells, which contributes to immune evasion. This study explored how mesothelin (MSLN), a tumor-associated antigen, modulates the expression of CD24, an emerging target for immune modulation, and its role in promoting immune evasion in HGSOC. Understanding these underlying mechanisms is crucial for enhancing the efficacy of immune checkpoint blockade (ICB) therapies and improving outcomes in patients with HGSOC.Methods We analyzed the expression of MSLN in HGSOC samples and examined its correlation with clinical outcome. In vitro and in vivo models were used to explore how MSLN influences CD24 expression and the polarization of tumor-associated macrophages (TAMs). We also investigated the role of MSLN in the activation of Wnt/beta-catenin signaling and its impact on T-cell function and antitumor immunity. The effects of Msln knockdown on CD24 expression and the response to anti-programmed cell death protein-1 (PD-1) therapy were evaluated in syngeneic mouse models.Results MSLN expression was found to be significantly elevated in HGSOC, with high MSLN levels correlating with poor prognosis and resistance to ICB. MSLN upregulated CD24 and promoted the protumorigenic polarization of TAMs, contributing to T-cell dysfunction. Mechanistically, MSLN activated Wnt/beta-catenin signaling, which in turn enhanced CD24 expression. This activation forms a positive feedback loop that further promotes MSLN transcription. In contrast, Msln knockdown reduced CD24 expression, relieved cytotoxic T-cell suppression, and significantly improved the efficacy of anti-PD-1 therapy in syngeneic models.Conclusions This study elucidates the critical role of MSLN in immune evasion in HGSOC and its underlying mechanisms. Targeting MSLN in combination with ICB is a promising strategy to enhance the efficacy of immunotherapy and improve patient outcomes in HGSOC.