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Background mCRPC is an advanced disease stage where, regardless of testosterone-castration, the disease shows a more aggressive phenotype refractory to systemic treatment and remains incurable. STAR0602 is a novel anti-TCR Vb6 targeted antibody fused to IL-2 capable of inducing potent anti-tumor effect by expanding Vb6 + CD8+ memory T cells. To date, STAR0602 is being evaluated in a Phase 1/2 clinical trial (NCT05592626) for the treatment of advanced solid tumors and preliminary results have shown clinical benefit in heavily pre-treated and anti-PD-1 resistant cancer patients. Our study tested the hypothesis that combination of mSTAR1302, the murine surrogate of STAR0602, with Olaparib, will achieve a robust anti-tumor efficacy in prostate cancer models.Methods Using TRAMP-C2 and RM-1, both syngeneic murine prostate cancer models classified as immunologically ‘cold’ tumors, we assessed anti-tumor activity and survival benefit after combination therapy. To determine the requirement of a subset of immune cells (NK cells, CD4 +, CD8+, and Vb13+ T cells) or the demand of IFN-g for the therapeutic efficacy of combination therapy, depletion studies were performed. Finally, tumors were harvested for flow cytometry and RNA expression analyses.Results In vivo studies demonstrated that mSTAR1302 plus Olaparib combination therapy elicited a significant tumor suppression of TRAMP-C2 and RM-1 tumors compared to mSTAR1302 or Olaparib monotherapies. In both models, combination therapy resulted in survival benefit. Depletion studies showed the requirement of CD4 +, CD8+, and Vb13+ T cells and NK cells for combination therapy to suppress TRAMP-C2 tumor growth. Moreover, we demonstrated that Olaparib upregulates the expression of death receptor TRAIL-R2 in TRAMP-C2 tumor cells sensitizing them to killing.Conclusions In summary, mSTAR1302 plus Olaparib combination therapy was shown to modulate the immune response, thereby achieving a robust anti-tumor effect. This data strongly supports the rationale for the design of clinical trials in mCRPC using combination therapy.Ethics Approval All animal studies were performed according to approved NIH Intramural Animal Care and Use Committee protocol (CIO-02). All mice were housed and maintained in accordance with the Association for Assessment and Accreditation of Laboratory Animal Care guidelines.