Synergistic effects of HO-1 inhibition and chemotherapy on tumor proliferation and immune infiltration: An in vitro and in vivo approach to enhancing prostate cancer treatment

Abstract

Prostate cancer (PC) remains a leading cause of morbidity and mortality among men worldwide, highlighting the need for novel therapeutic strategies. Our study investigates the therapeutic potential of targeting the heme degradation pathway through heme oxygenase-1 (HO-1) inhibition in PC. Using both in vitro and in vivo models, we explored the effects of combining HO-1 inhibition with chemotherapy, represented by docetaxel (Doc), on tumor growth and immune infiltration. In vitro experiments demonstrated that HO-1 inhibition, as well as HO-1 knockout (KO), significantly reduced tumor cell proliferation and enhanced chemosensitivity in RM-1 cells. Additionally, U937 cells co-cultured with HO-1 KO cells shifted cell polarization toward an M1 phenotype. In vivo, the combined treatment of the HO-1 inhibitor, tin protoporphyrin (SnPP), with Doc significantly enhanced anti-tumor efficacy in mouse models compared to chemotherapy or SnPP alone. This combination therapy not only reduced Ki67 expression and increased CC3 expression in tumor tissues but also shifted macrophage polarization toward an M1 phenotype and enhanced CD4⁺ and CD8⁺ T cells infiltration, indicating an augmented immune response. Further investigation using macrophage-specific HO-1 knockout mice revealed a direct role of HO-1 inhibition in driving macrophage polarization, confirming its involvement in promoting the shift toward an M1 phenotype. Although this response was significant, it was more robust with systemic HO-1 inhibition. Our findings indicate that HO-1 inhibition can potentiate the effects of chemotherapy, offering a promising avenue for improving PC treatment outcomes.