A phase 1 trial evaluated the safety and efficacy of PSCA-directed CAR T cells in patients with metastatic castration-resistant prostate cancer (mCRPC). The study included three dose levels (DLs): DL1 (100 million CAR T cells without lymphodepletion), DL2 (100 million CAR T cells with lymphodepletion), and DL3 (reduced lymphodepletion). No dose-limiting toxicities (DLTs) were observed in DL3. Cytokine release syndrome (CRS) occurred in 5 of 14 patients, with grades 1 or 2. Prostate-specific antigen (PSA) levels declined in 4 of 14 patients, and radiographic improvements were observed in some. Dynamic changes in immune cell subsets, TCR repertoire diversity, and the tumor immune microenvironment were noted in some patients. CAR T cells showed limited persistence beyond 28 days post-infusion. The study supports further clinical trials to optimize dosing and combination strategies for improved therapeutic outcomes. mCRPC is a lethal disease with limited treatment options. Immunotherapy has shown limited success, and only sipuleucel-T has been proven to prolong survival. PSCA and PSMA are potential targets for immunotherapy. CAR T cell therapies have shown success in hematological malignancies, prompting their development for mCRPC. PSCA is highly expressed in prostate cancer and increases with disease progression. Preclinical studies showed safety and efficacy of second-generation PSCA-CAR T cells. The phase 1 trial demonstrated safety and early clinical responses, with PSA declines and radiographic improvements in some patients. CAR T cell persistence was limited, and toxicity was managed with reduced lymphodepletion. The study highlights the potential of PSCA as a CAR T cell target and supports further research to improve therapeutic outcomes.A phase 1 trial evaluated the safety and efficacy of PSCA-directed CAR T cells in patients with metastatic castration-resistant prostate cancer (mCRPC). The study included three dose levels (DLs): DL1 (100 million CAR T cells without lymphodepletion), DL2 (100 million CAR T cells with lymphodepletion), and DL3 (reduced lymphodepletion). No dose-limiting toxicities (DLTs) were observed in DL3. Cytokine release syndrome (CRS) occurred in 5 of 14 patients, with grades 1 or 2. Prostate-specific antigen (PSA) levels declined in 4 of 14 patients, and radiographic improvements were observed in some. Dynamic changes in immune cell subsets, TCR repertoire diversity, and the tumor immune microenvironment were noted in some patients. CAR T cells showed limited persistence beyond 28 days post-infusion. The study supports further clinical trials to optimize dosing and combination strategies for improved therapeutic outcomes. mCRPC is a lethal disease with limited treatment options. Immunotherapy has shown limited success, and only sipuleucel-T has been proven to prolong survival. PSCA and PSMA are potential targets for immunotherapy. CAR T cell therapies have shown success in hematological malignancies, prompting their development for mCRPC. PSCA is highly expressed in prostate cancer and increases with disease progression. Preclinical studies showed safety and efficacy of second-generation PSCA-CAR T cells. The phase 1 trial demonstrated safety and early clinical responses, with PSA declines and radiographic improvements in some patients. CAR T cell persistence was limited, and toxicity was managed with reduced lymphodepletion. The study highlights the potential of PSCA as a CAR T cell target and supports further research to improve therapeutic outcomes.