Cancer cells hijack mitochondria from Bhlhe40+ T cells for immune evasion

CD38 regulates tunneling nanotube formation via CD31, and conditional Cd38 knockdown in murine models enables CD8+ T cell-dependent tumor shrinkage.

• Why it matters: Mitochondrial loss from T cells via TNTs supports cancer immune evasion, but the molecular control of TNT formation and mitochondrial transfer remains unclear.
• What they did: Targeted gene screening identified CD38 as a TNT regulator through CD31 interaction; tumor-infiltrating single-cell RNA-seq showed cancer preferentially targets the Bhlhe40+ effector subset.
• The result: The Bhlhe40–S100a4 cascade creates mitochondrial-loss vulnerability for tumor neoantigen-specific T cells, and dual blockade (Cd38 knockdown plus S100a4 inhibitor trifluoperazine) markedly suppressed tumor growth.