AKT inhibition with capivasertib counteracts tumor microenvironment remodeling and enhances AR-targeted therapy in PTEN-deficient prostate cancer

Background: PTEN loss in prostate cancer activates PI3K/AKT/mTOR signaling, driving extensive tumor microenvironment (TME) remodeling characterized by stromal desmoplasia, angiogenesis, and immune suppression. Capivasertib (AZD5363), a potent pan-AKT inhibitor, has shown therapeutic benefit in PTEN-deficient tumors when combined with androgen deprivation therapy (ADT) and abiraterone, as demonstrated in preclinical studies and the Phase III CAPItello-281 trial. Objective: To investigate how AKT inhibition modulates TME dysregulation in PTEN-deficient prostate cancer following AR-targeted therapy. Methods: Conditional Pten-knockout mouse tumors underwent baseline transcriptomic profiling to characterize AKT-driven changes and ADT effects. TME responses were evaluated in conditional Pten/Trp53 knockout mice after four weeks of ADT and abiraterone (Abi), with or without capivasertib. Analyses included qRT-PCR panels, flow cytometry, and quantitative immunohistochemistry (IHC). Results: PTEN deletion induced AKT hyperactivation and upregulated MSigDB hallmark pathways associated with TME remodeling, including hypoxia, angiogenesis, inflammatory response, IL6-STAT3, and TGFbeta signaling. ADT amplified these changes, while abiraterone further increased extracellular matrix (ECM) remodeling gene expression. Capivasertib co-treatment significantly downregulated ECM and angiogenesis-related genes. Histological evaluation revealed reduced dense, haphazard collagen deposition and fewer inflammatory infiltrates in capivasertib-treated tumors. IHC confirmed decreased stromal p-S6 and p-PRAS40, lower Ki67-positive stromal cell counts, and reduced microvessel density (CD31). Gene signatures for PMN cells, MDSCs, and TAMs-key mediators of ECM remodeling-were diminished, particularly in mice showing strong antitumor responses to capivasertib. Flow cytometry and IHC corroborated the reduction of PMN/MDSC populations in treated tumors. Conclusion: Capivasertib enhances tumor growth inhibition achieved by ADT plus abiraterone and mitigates TME remodeling associated with PTEN loss and AR-targeted therapy. These findings highlight AKT inhibition as a strategy to counteract TME-driven disease progression and improve therapeutic outcomes.