The E2F1-HMGCR axis promotes ferroptosis resistance in immune refractory tumor cells
During cancer immunoediting, cancer cells deregulate cell death executioner mechanisms to escape immunotherapy-induced antitumor immunity. Ferroptosis, a type of regulated necrosis triggered by lipid peroxidation, plays a pivotal role in the anti-tumor activity of T cell-based immunotherapies; however, mechanisms for the modulation of ferroptosis in immune-refractory tumor cells are unclear. In this study, using preclinical models of immune refractory tumors obtained following the course of immunoediting by PD-1 blockade and adoptive T cell therapy (ACT), we find that T cell-based immunotherapy drives the development of ferroptosis resistance of tumor cells. In this process, E2F1 is upregulated by immunotherapy and it in turn binds to the promoter of the HMGCR gene to upregulate HMGCR, thereby contributing to the resistance to ferroptosis. Notably, HMGCR inhibition renders immune-refractory tumor cells susceptible to ACT and PD-1 blockade. Thus, our results reveal a mechanism by which cancer cells modulate ferroptosis to acquire resistance to immunotherapy and implicate the E2F1-HMGCR axis as a central molecular target for controlling ferroptosis resistance of immune-refractory cancer.
Authors
- Seung‐Ho Lee (ORCID: https://orcid.org/0000-0002-7840-422X)
- NaNa Kang
- Sung Wook Son
- Seon Rang Woo (ORCID: https://orcid.org/0000-0003-2640-5025)
- Cassian Yee (ORCID: https://orcid.org/0000-0002-4429-7307)
- Kyung‐Mi Lee (ORCID: https://orcid.org/0000-0002-5378-9258)
- Young‐Chae Chang (ORCID: https://orcid.org/0000-0003-2667-7303)
- Eun‐Woo Lee (ORCID: https://orcid.org/0000-0002-5156-0003)
- Jong-Young Kwak (ORCID: https://orcid.org/0000-0003-4393-5140)
- Jisu Chae (ORCID: https://orcid.org/0000-0003-0343-8190)
- Cheol Kwak (ORCID: https://orcid.org/0000-0002-1987-2111)
- Kwon‐Ho Song (ORCID: https://orcid.org/0000-0001-6547-1143)
- Dayoung Yoon (ORCID: https://orcid.org/0000-0002-9985-2945)
- Seongjae Bae
- Chaeleen Lee
- Hee‐Jung Choi (ORCID: https://orcid.org/0000-0002-1167-1526)
- Yun‐Jeong Jeong (ORCID: https://orcid.org/0000-0001-9144-7403)
- Suyeon Kim (ORCID: https://orcid.org/0000-0002-3691-7692)
- Tae‐Woo Kim (ORCID: https://orcid.org/0000-0002-5180-0978)
- Eunho Cho (ORCID: https://orcid.org/0000-0002-3409-2535)
- Se Jin Oh (ORCID: https://orcid.org/0000-0002-9591-5267)
- Jinuk Park (ORCID: https://orcid.org/0000-0003-0424-8225)
- Younji Sim (ORCID: https://orcid.org/0009-0002-4988-8912)
- Hyo-Jung Lee
- Heeju Kwon
- Min Kyu Son
Institutions
- The University of Texas MD Anderson Cancer Center (US)
- Korea University (KR)
- Daegu Catholic University (KR)
- Daegu Catholic University Medical Center (KR)
- NovaCell Technology (South Korea) (KR)
- Korea University (JP)
- Ajou University (KR)
- Korea Research Institute of Bioscience and Biotechnology (KR)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-12-03
- DOI
- https://doi.org/10.1038/s41467-025-66282-x
- Citations
- 1
- Primary Topic
- Ferroptosis and cancer prognosis
- Type
- article
- Field-Weighted Citation Impact
- 1.52
Funders
- National Research Foundation
- National Research Foundation of Korea