The study investigates the role of INHBA(+) cancer-associated fibroblasts (CAFs) in ovarian cancer progression and immunosuppression. Key findings include: 1. **Expression and Clinical Significance**: INHBA is upregulated in ovarian cancer and associated with poor patient survival. INHBA(+) CAFs are enriched in metastatic and recurrent tumors, and their ratio correlates with the presence of regulatory T cells (Tregs). 2. **Mechanisms of Action**: INHBA(+) CAFs promote tumor progression by recruiting and differentiating Tregs through a contact-mediated mechanism. They also upregulate PD-L1 expression, which facilitates Treg differentiation via SMAD2-dependent signaling. 3. **In Vivo Models**: Neutralizing Activin A in syngeneic mouse models of ovarian cancer reduced tumor growth, infiltration of pro-tumorigenic fibroblasts, and macrophages, while increasing the number of immune cells. 4. **In Vitro Studies**: Downregulation of INHBA in CAFs inhibited their pro-tumorigenic functions, including collagen gel contraction, cell proliferation, and invasion. Activin A increased PD-L1 expression in CAFs through SMAD2-dependent transactivation of the PD-L1 promoter. 5. **Therapeutic Implications**: Targeting INHBA(+) CAFs, particularly through Activin A neutralization, may be a potential therapeutic strategy for advanced ovarian cancers, as it could enhance the efficacy of immunotherapies. The study highlights the potential of targeting INHBA(+) CAFs as a novel therapeutic approach to improve outcomes in ovarian cancer, which often shows poor response to immunotherapy.The study investigates the role of INHBA(+) cancer-associated fibroblasts (CAFs) in ovarian cancer progression and immunosuppression. Key findings include: 1. **Expression and Clinical Significance**: INHBA is upregulated in ovarian cancer and associated with poor patient survival. INHBA(+) CAFs are enriched in metastatic and recurrent tumors, and their ratio correlates with the presence of regulatory T cells (Tregs). 2. **Mechanisms of Action**: INHBA(+) CAFs promote tumor progression by recruiting and differentiating Tregs through a contact-mediated mechanism. They also upregulate PD-L1 expression, which facilitates Treg differentiation via SMAD2-dependent signaling. 3. **In Vivo Models**: Neutralizing Activin A in syngeneic mouse models of ovarian cancer reduced tumor growth, infiltration of pro-tumorigenic fibroblasts, and macrophages, while increasing the number of immune cells. 4. **In Vitro Studies**: Downregulation of INHBA in CAFs inhibited their pro-tumorigenic functions, including collagen gel contraction, cell proliferation, and invasion. Activin A increased PD-L1 expression in CAFs through SMAD2-dependent transactivation of the PD-L1 promoter. 5. **Therapeutic Implications**: Targeting INHBA(+) CAFs, particularly through Activin A neutralization, may be a potential therapeutic strategy for advanced ovarian cancers, as it could enhance the efficacy of immunotherapies. The study highlights the potential of targeting INHBA(+) CAFs as a novel therapeutic approach to improve outcomes in ovarian cancer, which often shows poor response to immunotherapy.