Inherited mitochondrial genetics as a predictor of immune checkpoint inhibition efficacy in melanoma

作者：Kelsey R. Monson, Robert Ferguson, Joanna E. Handzlik, Leah Morales, Jiahan Xiong, Vylyny Chat, Sasha Dagayev, Alireza Khodadadi‐Jamayran, Danny Simpson, Esther Kazlow, Anabelle Bunis, Chaitra Sreenivasaiah, Milad Ibrahim, Iryna Voloshyna, Wouter Ouwerkerk, Rosalie M. Luiten, Mariaelena Capone, Gabriele Madonna, Yuting Lu, Yongzhao Shao, Anna C. Pavlick, Michelle Krogsgaard, Janice M. Mehnert, Hao Tang, Sonia Dolfi, Daniel J. Tenney, John B.A.G. Haanen, Thomas F. Gajewski, F. Stephen Hodi, Keith T. Flaherty, Kasey L. Couts, William H. Robinson, Igor Puzanov, Marc S. Ernstoff, Osama E. Rahma, Michael A. Postow, Ryan J. Sullivan, Jason J. Luke, Paolo A. Ascierto, Iman Osman, Tomas Kirchhoff · 发表于：Nature Medicine · 年份：2025 · DOI：10.1038/s41591-025-03699-3 · 被引用次数：12 · 研究领域：Cancer Immunotherapy and Biomarkers、Immunotherapy and Immune Responses、CAR-T cell therapy research

Abstract Response to immune checkpoint inhibitors (ICIs) in metastatic melanoma (MM) varies among patients, and current baseline biomarkers predicting treatment outcomes are limited. As mitochondrial (MT) metabolism has emerged as an important regulator of host immune function, we explored the association of host MT genetics (MT haplogroups) with ICI efficacy in 1,225 ICI-treated patients with MM from the clinical trial CheckMate-067 and the International Germline Immuno-Oncology Melanoma Consortium. We discovered and validated significant associations of MT haplogroup T (HG-T) with resistance to anti-programmed cell death protein-1-based ICI (both single-agent and combination) and have shown that HG-T is independent from established tumor predictors. We also found that patients belonging to HG-T exhibit a unique nivolumab-resistant baseline peripheral CD8 + T cell repertoire compared to other MT haplogroups, providing, to our knowledge, the first link between MT inheritance, host immunity and ICI resistance. The study proposes a host blood-based biomarker with stand-alone clinical value predicting ICI efficacy and points to an ICI-resistance mechanism associated with MT metabolism, with clinical relevance in immuno-oncology.