Kitasamycin Overcomes Ferroptosis and Immunotherapy Resistance by Targeting  HUWE1-NCOA4-FTH1Axis (PRJCA046017)
Clinicians typically avoid antibiotics use during immunotherapy due to concerns about reduced efficacy. However, cancer patients requiring antibiotics postoperatively or for infections urgently need options that provide antimicrobial coverage while potentially enhancing, rather than impair immunotherapy. Restoring ferroptosis susceptibility represents a promising strategy to overcome immunotherapy resistance, yet the role of antibiotics in modulating ferroptosis and interacting with ICB remains unexplored. In this study, we screened 96 FDA-approved antibiotics across seven pharmacological classes and identified the macrolide kitasamycin as a specific and potent ferroptosis sensitizer in vitro and in vivo. Mechanistically, kitasamycin binds to HUWE1, inhibiting its E3 ubiquitin ligase activity, which stabilizes NCOA4 and activates the NCOA4-FTH1 ferritinophagy axis. Single-cell transcriptomics, flow cytometry, and multiplex immunohistochemistry revealed that kitasamycin induces immunogenic ferroptosis and reshapes anti-tumor T cell immunity. Critically, kitasamycin potentiated immune checkpoint blockades (ICBs)-mediated ferroptosis and overcame ICB resistance across diverse preclinical melanoma models: B16F10 tumor-bearing mice, Braf/Pten-driven spontaneous melanoma, and PBMC-humanized mice. Clinically, a high NCOA4/low HUWE1 signature correlated with ferroptosis activation, increased T-cell infiltration, and improved survival in ICB-treated patients, suggesting its potential as a predictive biomarker. Our findings position kitasamycin as a promising adjunct to immunotherapy for cancer patients requiring concurrent antibiotic therapy