Chronotherapy leveraging dietary context overcomes circadian rhythm influence on cancer cell response to PPAR antagonists.

Feeding–fasting nutrient context abolishes circadian time-of-day variability in colorectal cancer cell sensitivity to PPAR-γ antagonists, unifying responses across 2D/3D models.

• Why it matters: It is unclear whether feeding-fasting cycles or tumor-intrinsic clocks set tumor metabolic state and thereby shape drug sensitivity.
• What they did: The authors profiled CRC responses to PPAR-γ antagonists in 2D and 3D CRC models and tumor-bearing mice, comparing standard high-glucose, low-fat medium with nutrient-defined media that mimic feeding and nighttime fasting.
• The result: Nutrient-defined media removed time-dependent variability and unified drug responses, while the fed state selectively sensitized spheroids and patient-derived organoids; in mice, fed-state dosing prolonged survival and reduced hepatotoxicity, and Bmal1-silenced CRC cells supported feeding-fasting rhythms over tumor-intrinsic clocks.

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