An oral heme oxygenase inhibitor targets immunosuppressive perivascular macrophages in preclinical models of cancer.

A subset of perivascular tumor-associated macrophages (PvTAMs) expressing lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) relies on heme oxygenase-1 (HO-1) activity to maintain an immunologically cold tumor microenvironment, which suppresses the efficacy of chemotherapy. Consequently, HO-1 inhibition represents a strategy to target immunosuppressive LYVE-1(+) PvTAMs and improve therapeutic responses. We developed and characterized KCL-HO-1i, a small-molecule, orally bioavailable HO-1 inhibitor. In chemotherapy-resistant spontaneous murine MMTV-PyMT breast cancer and subcutaneous MN/MCA1 sarcoma models, targeting the PvTAM function with KCL-HO-1i enhanced chemotherapy effects and sensitized tumors to treatment. KCL-HO-1i combined with chemotherapy promoted an immunologically hot tumor microenvironment characterized by increased infiltration of CD8(+) T cells exhibiting effector function. These findings identify KCL-HO-1i as a nontoxic, orally bioavailable small-molecule immunotherapeutic targeting a key subset of protumoral PvTAMs, offering a combinatorial strategy to enhance chemotherapy efficacy in cancer.