We read with great interest the study by Yi Liu et al published in the International Journal of Surgery1, entitled “Distinct roles of HMOX1 on tumor epithelium and macrophage for regulation of immune microenvironment in ovarian cancer.” Employing comprehensive and rigorous research methods including multi-omics analysis and in vivo/in vitro experiments, the authors revealed the unique regulatory role of heme oxygenase 1 (HMOX1), a ferroptosis-related gene, in the ovarian cancer immune microenvironment. They confirmed that HMOX1 is lowly expressed in tumor epithelial cells and highly expressed in macrophages, and synergistically induces the differentiation of three macrophage subtypes through the NF-κB pathway, ultimately leading to PD-1 inhibitor resistance. From mechanistic dissection to therapeutic strategy exploration, this study provides a novel perspective for understanding the role of HMOX1 in ovarian cancer immunotherapy and lays a crucial foundation for the development of combination treatment regimens. While we fully acknowledge the scientific value and innovation of this work, there is room to further enhance its translational potential, and several points merit discussion. The HTSFC prediction model constructed by the authors (comprising HMOX1, TGF-β1, SPP1, FOLR2, and C1QC) demonstrates predictive value for the efficacy of PD-1 inhibitors. However, this model was built based on a limited number of clinical samples and lacks external validation in large-scale, multi-center cohorts. Incorporating ovarian cancer patient cohorts with different pathological types and clinical stages to validate the model’s applicability in diverse populations will help improve its credibility for clinical application. Additionally, although the study confirmed that HMOX1 regulates macrophage polarization through the TGF-β1/PI3K/AKT/NF-κB pathway, details regarding the interactions between key molecules in this pathway need to be supplemented – for instance, how the low expression of HMOX1 in tumor epithelial cells precisely regulates TGF-β1 secretion, and the specific molecular triggering mechanisms by which the high expression of HMOX1 in macrophages activates the NF-κB pathway, both of which require further verification through additional gain-of-function and loss-of-function experiments. The two combination therapeutic strategies proposed by the authors (ZnPP + TGF-β1 blocking antibody + PD-1 inhibitor, and carnosol + IMD0354 + PD-1 inhibitor) offer new ideas for overcoming the “double-edged sword effect” of HMOX1, but they have only been validated in mouse models to date. Considering the heterogeneity of clinical ovarian cancer and the differences between human and animal models, conducting preclinical organoid experiments or small-scale clinical trials to evaluate the safety and efficacy of these drug combinations will provide critical data for subsequent translational applications. Meanwhile, the study did not clarify the direct association between HMOX1 expression levels and the clinical prognosis of ovarian cancer patients. Supplementing the analysis of HMOX1 expression in patients with different clinical outcomes and its correlation with other clinicopathological indicators can further strengthen its clinical significance as a therapeutic target. The study adopted the ID8 mouse ovarian cancer model combined with validation in multiple cell lines, and the model construction is reasonable. However, the pathogenesis of clinical ovarian cancer is more complex, involving interactions among various cells in the tumor microenvironment and the influence of systemic factors. Validating HMOX1-related mechanisms in more clinically relevant models (such as patient-derived xenograft models) will help confirm the clinical applicability of the research findings2,3. Furthermore, the study focuses on the regulation of macrophage subtypes, while HMOX1, as a key ferroptosis gene, may also participate in the regulation of the immune microenvironment by affecting the functions of other immune cells (e.g., T cells, natural killer cells). Exploring the role of HMOX1 in other immune cells can provide supplements for a comprehensive understanding of its regulatory network. Accumulating evidence indicates that ferroptosis-related genes play multiple roles in tumor immunotherapy. In addition to HMOX1, genes such as GPX4 and SLC7A11 have also been confirmed to be associated with PD-1 inhibitor resistance4–7. Moreover, the regulation of HMOX1 expression may involve multiple levels including epigenetic modifications and non-coding RNA regulation. How these regulatory mechanisms affect its “double-edged sword effect” in ovarian cancer has not been fully explored. Integrating multi-omics technologies such as epigenomics and transcriptomics to conduct in-depth analysis of the upstream regulatory network of HMOX1 can provide a basis for the development of more precise targeted strategies. In conclusion, the study by Yi Liu et al provides highly valuable experimental evidence and therapeutic directions for ovarian cancer immunotherapy. As a key regulatory factor, HMOX1 holds great promise as a new target for ovarian cancer immunotherapy. Incorporating larger-scale clinical cohorts, supplementing the verification of key molecular mechanisms, and carrying out preclinical translational research will further enhance the translational value of this study. We commend the authors for their important contributions and look forward to future research advancing the development of precision immunotherapeutic strategies for ovarian cancer. This correspondence adheres to the TITAN 2025 guideline for transparency and integrity in translational and applied research. Ethical approval Not applicable. Consent Not applicable. Sources of funding This work was supported by the Youth Program of the Science and Education for Health Promotion Initiative of Suzhou (QNXM2025085), the Suzhou Applied Basic Research Science and Technology Innovation Program (SYWD2024201), the Science and Technology Development Outstanding Talent Fund of the Affiliated Hospital of Xuzhou Medical University (XYFY202423). Author contributions J.C.: Participated in the drafting of the initial draft of this letter; Y.Z.: Participated in the revision of this letter; R.M.: Participated in the writing and structural design of this letter. All authors have read and approved the final manuscript.
Chen et al. (Fri,) studied this question.