Targeting SPP1+ macrophages via the SPP1-CD44 axis reveals a key mechanism of immune suppression and tumor progression in ovarian cancer

Tumor-associated macrophages (TAMs) play a pivotal role in immune suppression, tumor progression, and metastasis within the tumor microenvironment (TME) of ovarian cancer. While TAMs are known to promote T-cell dysfunction, the precise molecular mechanisms governing this process remain poorly understood. Here, we performed an integrated analysis of six high-grade serous ovarian cancer (HGSOC) single-cell sequencing datasets to investigate the molecular and functional diversity of TAMs in HGSOC. We identified an SPP1+ TAM subpopulation enriched in HGSOC and strongly associated with poor prognosis. These macrophages promoted T-cell exhaustion via the SPP1-CD44 axis, which emerged as the principal mediator of immune suppression. Functional assays demonstrated that SPP1 secreted by TAMs drove T-cell exhaustion, weakening anti-tumor immunity. Blocking either SPP1 or CD44 effectively reversed T-cell exhaustion, restored CD8+ T-cell functionality, and suppressed tumor growth in vivo. Furthermore, molecular docking and dynamics simulations identified nilotinib as a potential SPP1 inhibitor, exhibiting strong binding affinity and stability. In vitro assays confirmed that nilotinib reduced PD-1 expression in Jurkat cells induced by M2-type macrophages, underscoring its therapeutic potential in reversing T-cell exhaustion in ovarian cancer. The research demonstrates that SPP1+ TAMs drive immune suppression and T-cell exhaustion in ovarian cancer via the SPP1-CD44 axis, highlighting this pathway as a promising therapeutic target for reprogramming the immune microenvironment and improving patient outcomes.