From dose to exposure? rethinking fluoropyrimidines as immune checkpoint partners in gastrointestinal cancers

Fluoropyrimidine regimens in gastrointestinal oncology have evolved empirically. Bolus 5-fluorouracil (5-FU)-containing combinations now coexist with continuous metronomic schedules and oral prodrugs, while immune checkpoint inhibitors (ICIs) seek chemotherapy partners for microsatellite-stable (MSS) gastrointestinal cancers. This review examines the intersection of bolus omission, metronomic scheduling, and biomarker-selected immunochemotherapy and proposes a shift from dose-based to exposure-based paradigms.

A real-world cohort of 11 765 patients showed that bolus omission from FOLFOX, FOLFIRI and FOLFIRINOX preserved survival and approximately halved grade 3-4 haematological toxicity. CAIRO3 validated low-dose continuous capecitabine maintenance, pharmacologically consistent with metronomic dosing. Preclinical murine studies suggest that fluoropyrimidine immune effects are dose-, schedule- and partner-dependent, with peak exposure activating NLRP3-driven pro-tumour pathways; relevance to human disease remains hypothetical. Two recent signals (POCHI and MEDITREME) share early-line treatment, immune or molecular enrichment, and an oxaliplatin-driven immunogenic cell death inducer; POCHI also avoids intravenous 5-FU bolus through its CAPOX backbone.

Recent failures of chemo-immunotherapy in MSS gastrointestinal cancers may partly reflect immunologically suboptimal chemotherapy backbones. Optimal outcomes likely require joint consideration of schedule, biomarker selection, and immunogenic partner. Prospective trials testing chemotherapy schedules are warranted.