Post-ICB Lymphocyte Stability Following Immune Checkpoint Blockade Is Coupled to Mitochondrial Haplotype and Clinical Outcome in Advanced Melanoma

In metastatic melanoma patients, unstable lymphocyte stability after one ICB cycle (LS-U; post-ICB/baseline ≤0.8) is linked to markedly increased overall survival risk.

• Why it matters: Durable response biomarkers for immune checkpoint blockade are needed to identify patients likely to benefit early and guide treatment decisions.
• What they did: The study measured lymphocyte stability after one ICB cycle, profiled patient T-cell metabolism, and tested links between LS and mitochondrial haplogroup using mediation analysis and paired scRNA-seq.
• The result: Mitochondrial haplogroup T (HG-T; ~10% of white British individuals) is associated with LS-U and impaired OS, and scRNA-seq shows HG-T carriers have baseline mitochondrial priming with fewer progenitor-exhausted cells and reduced clonal persistence after ICB.

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