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Preprint WatchMildOctober 29th, 2026

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

Hu, H.; Tan, Y.; Shkundina, I.; Madnick, R.; Hu, J.; Zhang, H.; Yang, Z.; Wang, T.; Yu, X.; Fleming, J.; Pan, M.; Wang, Y.; Pang, Y.; Weissman, D.; Li, B.

CD38 regulates tunneling nanotube formation through interaction with CD31, allowing cancer cells to hijack mitochondria from Bhlhe40-positive T cells, and conditional Cd38 knockdown produces CD8 T cell-dependent effects in murine models.

Mild contradiction

1 prior failure

One documented clinical failure (Phase 1 or 2) overlaps with the claimed mechanism.

Claidex records the CD38 HexaBody GEN3014 in relapsed or refractory multiple myeloma as a Phase 1/2 portfolio shutdown (gen3014-hexabody-cd38-rrmm-portfolio-shutdown). This preprint assigns CD38 a role in immune evasion that is separate from its role as a surface antigen for antibody-mediated killing, and that distinction matters for how a CD38-directed agent should be evaluated. If CD38 also mediates mitochondrial transfer from T cells, then depleting CD38-positive cells and blocking CD38 function have different immunological consequences. Trials of CD38-directed agents should measure T cell mitochondrial content alongside tumour response.

Abstract excerpt

Cancer cells hijack mitochondria from T cells via tunneling nanotubes (TNTs) to promote immune evasion, yet the underlying mechanisms of mitochondrial-loss remain poorly understood. Here, through targeted screening of relevant genes, we demonstrated that CD38 is a potent regulator of TNT formation through interaction with its cognate ligand, CD31. Conditional knockdown of Cd38 in murine models leads to CD8+ T cell-dependent tumor shrinkage. Single-cell RNA sequencing of tumor-infiltrating T cells revealed that cancer cells preferentially target the Bhlhe40+ effector subset. Bhlhe40 is a transcription factor that upregulates the expression of S100a4, a reported chemoattractant of nanotubes. Bhlhe40 upregulation creates mitochondrial-loss vulnerability for tumor neoantigen-specific T cells. Dual mitochondria transfer blockade with Cd38 knockdown and S100a4 inhibitor trifluoperazine markedly suppressed tumor growth. Collectively, our findings identified the Bhlhe40-S100a4 cascade as a critical regulator of cancer/T cell mitochondrial transfer, providing insights for the development of new cancer immunotherapies.

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This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.