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.