Sickle cell disease induces chromatin introversion and ferroptosis in CD8+ T cells to suppress anti-tumor immunity

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.