Mechanism-based precision pharmacology of natural products for triple-negative breast cancer: translational opportunities for targeted therapeutics.

Abstract

Triple-negative breast cancer (TNBC) remains one of the most therapeutically challenging malignancies because of its pronounced molecular heterogeneity, aggressive progression, and frequent development of resistance to chemotherapy, targeted agents, and immunotherapy. Natural products offer a distinctive medicinal chemistry resource because their structurally diverse scaffolds can engage multiple oncogenic and immune-regulatory targets simultaneously; however, their potential in TNBC has largely been discussed in conventional descriptive reviews that catalog individual compounds and mechanisms without establishing a clinically actionable framework for their integration into precision therapy. This review addresses this gap by developing a mechanism-based precision pharmacology framework that connects natural-product chemical scaffolds, multitarget molecular mechanisms, TNBC vulnerabilities, and rational therapeutic combinations. We critically examine representative phytochemicals according to their ability to modulate clinically actionable pathways, including PI3K/AKT/mTOR, receptor tyrosine kinases (RTKs), poly(ADP-ribose) polymerase (PARP), programmed death-1/programmed death-ligand 1 (PD-1/PD-L1), androgen receptor (AR), and trophoblast cell surface antigen-2 (TROP-2), and relate these mechanisms to the molecular heterogeneity of TNBC. Particular emphasis is placed on how multitarget natural-product scaffolds may complement contemporary targeted therapies, antibody-drug conjugates, immunotherapies, and chemotherapy through pathway-directed and subtype-informed combinations. We further critically evaluate preclinical and clinical evidence to identify the major barriers limiting translation, including poor bioavailability, unfavorable pharmacokinetics, insufficient target engagement, suboptimal formulation, and the lack of biomarker-guided patient selection. Rather than viewing natural products as nonspecific complementary agents, we propose their repositioning as chemically defined multitarget pharmacological modulators whose therapeutic value can be optimized through structure-informed development, pharmacodynamic validation, molecular stratification, and rational combination design. Finally, we propose a precision pharmacology roadmap linking natural-product scaffold, molecular vulnerability, pharmacological mechanism, rational combination, pharmacodynamic biomarker, and biomarker-enriched clinical evaluation. By integrating medicinal chemistry, molecular pharmacology, and translational oncology, this review provides a distinct framework for advancing natural-product-derived therapeutics from broad anticancer activity toward mechanism-driven precision medicine in TNBC.