Circadian engineering of in vivo CAR T cell therapy for precision oncology.

Circadian rhythms shape antitumor immunity by regulating endocrine signaling, vascular permissiveness, leukocyte trafficking, metabolism, and suppressive features of the tumor microenvironment across the 24-h cycle. Here, we propose that biological time may represent an important design variable for CAR T-cell therapy. This concept may be particularly relevant to in vivo CAR T platforms, which could extend temporal control beyond infusion timing through repeatable induction, tunable amplitude, and reversible shutdown. We discuss evidence that CD8⁺ T-cell clocks, neuroendocrine oscillations, endothelial gatekeeping, and rhythmic tumor-microenvironment remodeling influence immune access, effector competence, exhaustion risk, and inflammatory toxicity. We further examine how viral vectors, lipid nanoparticles, and programmable control circuits might enable circadian-aware CAR installation and duty-cycling. Together, these observations support chrono-synthetic CAR T as a testable translational framework for precision immuno-oncology.