Sickle Cell Disease Induces Chromatin Introversion and Ferroptosis in CD8+ T Cells To Suppress Anti-Tumor Immunity

Authors

• Zilong Zhao
• Benxia Hu
• Yalan Deng
• Melinda Soeung
• Jun Yao
• Lanxin Bei
• Yaohua Zhang
• Pengju Gong
• Lisa A Huang
• Zhou Jiang
• Jian Gao
• Shuang Peng
• Tina K Nguyen
• Menuka Karki
• Bora Lim
• Cassian Yee
• Jared K Burks
• Qing Zhang
• Li Ma
• Jianjun Gao
• Nizar M Tannir
• Leng Han
• Dihua Yu
• Linghua Wang
• Michael A Curran
• Maria A Gubbiotti
• Giannicola Genovese
• Boyi Gan
• Wenbo Li
• Pavlos Msaouel
• Liuqing Yang
• Chunru Lin

Language

English

Publication Date

6-10-2025

Journal

Immunity

DOI

10.1016/j.immuni.2025.04.020

PMID

40359940

PMCID

PMC12186235

PubMedCentral® Posted Date

6-10-2026

PubMedCentral® Full Text Version

Author MSS

Abstract

Understanding how genetic disorders affect CD8+ T cells in the tumor microenvironment is key to improving cancer immunotherapy. Individuals with sickle cell disease (SCD), the most prevalent inherited blood disorder, have a higher risk of developing certain cancers than the general population, but the mechanisms driving this increased risk remain unclear. Our study revealed that SCD altered CD8+ T cell 3D genome architecture, triggering ferroptosis and weakening anti-tumor immunity, thereby promoting tumor growth. Using murine and humanized SCD models, we found that disrupted chromosomal interactions in CD8+ T cells reduced the expression of anti-ferroptotic genes, including SLC7A11 and hydrogen sulfide (H2S) biogenesis genes, thereby increasing susceptibility to ferroptosis. Therapeutic restoration of H2S concentration in SCD mice rescued SLC7A11 expression, mitigated ferroptosis, and enhanced immune and anti-tumor responses. These findings highlight the impact of inherited disorders on cancer immunity and suggest precision immunotherapy strategies for affected individuals.

Keywords

Ferroptosis, Animals, CD8-Positive T-Lymphocytes, Mice, Anemia, Sickle Cell, Humans, Chromatin, Tumor Microenvironment, Amino Acid Transport System y+, Neoplasms, Disease Models, Animal, Mice, Inbred C57BL, Sickle Cell Disease, Renal Medullary Carcinoma, Ferroptosis, Genomic Architecture Alteration, Hi-C, H2S, SLC7A11, SMARCB1

Published Open-Access

yes

Recommended Citation

Zhao, Zilong; Hu, Benxia; Deng, Yalan; et al., "Sickle Cell Disease Induces Chromatin Introversion and Ferroptosis in CD8+ T Cells To Suppress Anti-Tumor Immunity" (2025). Faculty, Staff and Student Publications. 6854.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/6854