Adoptive T-cell therapies, including chimeric antigen receptor T-cell (CAR-T) and tumor-infiltrating lymphocyte (TIL) products, fail in solid tumors largely because effector cells become metabolically exhausted in the tumor microenvironment. Two convergent observations from independent fields make this failure mode mechanistically tractable: first, T-cell exhaustion is preceded and partly caused by mitochondrial insufficiency; second, tumor cells actively hijack mitochondria from infiltrating CD8+ T-cells through tunneling nanotubes (TNT). Pharmacological strategies that protect or reinforce T-cell mitochondria before adoptive transfer therefore represent a potentially high-leverage intervention point. Methylene blue (MB) is a century-old phenothiazine compound with extensive safety data and a unique mechanism: at sub-micromolar to low micromolar concentrations, MB acts as an alternative electron carrier in the mitochondrial electron transport chain, bypassing complex I/III bottlenecks, increasing ATP production, and reducing reactive oxygen species leakage. We propose that ex vivo MB pretreatment of CAR-T, TIL, or CAR-NK products will increase mitochondrial spare respiratory capacity, delay exhaustion-associated transcriptional programs, and reduce the functional impact of TNT-mediated mitochondrial loss. The hypothesis is mechanistically grounded, operationally testable with existing reagents and models, and addresses a recognized clinical bottleneck. We outline specific predictions, a tiered preclinical experimental program, candidate clinical translation paths, and falsification criteria. This is a hypothesis and theory paper containing no original experimental data. The author is an independent researcher seeking laboratory collaboration to test the proposed program. This document is research strategy and idea exploration, not medical advice or treatment recommendation.
Rickard Winbergh (Tue,) studied this question.