Synergistic, Additive, and Antagonistic Modulation of Inflammation and Immunity by Multi-Compound Traditional Chinese Medicine Formulas

Clinically used TCM formulas deliver multiple bioactive compound classes, saponins, flavonoids, alkaloids, polysaccharides, polyphenols, phenylpropanoids, and quinones, across overlapping inflammatory and immune targets. How these combinations interact, producing synergistic, additive, or antagonistic outcomes, remains systematically uncharacterized, limiting evidence-based formula optimization and clinical translation. PubMed, Web of Science, ScienceDirect, CNKI, and Google Scholar were searched from January 2018 to March 2026. Synergy is operationally defined as CI 1. Records were deduplicated in Rayyan; two reviewers independently selected 50 studies from approximately 11,886 records per pre-specified PRISMA criteria, with evidence stratified throughout by study type. Saponins and alkaloids converge on TLR4/NF-κB and NLRP3 inflammasome suppression; flavonoids and polyphenols attenuate MAPK and COX-2 signaling; polysaccharides promote Treg differentiation while restraining Th17 activity; phenylpropanoids regulate TNF-α and IL-6 transcriptionally; and tanshinone IIA targets TLR4/TAK1/NF-κB and iNOS. In preclinical models, berberine and Astragalus polysaccharides engage mechanistically non-redundant targets (TLR4/NF-κB, Nrf2, and Treg/Th17 axis), constituting pharmacodynamic convergence without formal CI quantification. In a meta-analysis of 18 RCTs (n = 1,600), berberine supplementation significantly reduced serum TNF-α (WMD -3.72 pg/mL); Astragaloside IV independently suppressed TNF-α and IL-1β in adjuvant-induced arthritis rats. Synergies operate through physicochemical, pharmacokinetic, and pharmacodynamic dimensions. Antagonistic interactions remain critically underreported. Available evidence indicates that multi-compound TCM formulas frequently produce outcomes not predictable from isolated constituent studies alone, though the evidence base is predominantly preclinical. Standardized combination-index quantification, systematic antagonism reporting, and pharmacokinetic–pharmacodynamic integration are essential for regulatory-defensible clinical translation.