2. Academic Validation
  3. An oral heme oxygenase inhibitor targets immunosuppressive perivascular macrophages in preclinical models of cancer

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

  • Sci Transl Med. 2025 Aug 6;17(810):eads3085. doi: 10.1126/scitranslmed.ads3085.
Meriem Bahri 1,  Taha Al-Adhami 2,  Emre Demirel 1 2,  Jit Sarkar 1,  Karen T Feehan 1,  Joanne E Anstee 1,  Tik Shing Cheung 1,  Dominika Sosnowska 1,  Chloé A Woodman 1,  William Macmorland 1,  Dorothy D Yang 1,  James Rosekilly 1,  Renee Gitsaki-Taylor 1,  Cheryl E Gillett 1,  Cheryl L Scudamore 3,  James Spicer 1,  Khondaker Miraz Rahman 2,  James N Arnold 1
Affiliations

Affiliations

  • 1 School of Cancer and Pharmaceutical Sciences, King's College London, London SE1 1UL, UK.
  • 2 Institute of Pharmaceutical Sciences, King's College London, London SE1 9NH, UK.
  • 3 ExePathology, Exmouth EX81TN, UK.
PMID: 40768602 DOI: 10.1126/scitranslmed.ads3085
Abstract

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.

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