Tanshinone IIA in colorectal cancer: preclinical mechanisms, therapeutic sensitization, and translational prospects

Colorectal cancer (CRC) remains a major global health burden, with recurrence, metastasis, and therapeutic resistance limiting durable treatment responses. Tanshinone IIA (Tan IIA), a bioactive diterpene quinone derived from Salvia miltiorrhiza Bunge, has shown broad antitumor activity in preclinical CRC models. This review summarizes its major mechanisms, therapeutic-sensitization effects, and translational potential, while evaluating mechanistic evidence using a three-tier framework encompassing association, functional evidence, and mechanistically supported causality. Tan IIA inhibits proliferation, promotes apoptosis, disrupts mitochondrial and redox homeostasis, suppresses glycolytic adaptation, and modulates autophagy, ferroptosis, invasion, angiogenesis, and the inflammatory tumor microenvironment. It also enhances sensitivity to 5-fluorouracil and oxaliplatin in selected resistant models. Despite these preclinical findings, a substantial exposure gap exists between the nominal concentrations commonly used in CRC cell studies (5–40 μM) and the total plasma peak concentrations reported after oral Danshen administration in healthy volunteers (1.75–25.76 ng/mL). Clinical translation remains challenged by poor aqueous solubility, limited systemic exposure, metabolic clearance, and insufficiently defined exposure–response relationships and safety windows. Future studies should prioritize mechanistic validation and the assessment of pharmacologically active intratumoral exposure, alongside formulation optimization, structural modification, and systematic safety evaluation.