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
  • 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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