<p>Metal polyphenol nanocomplexes (MPNs) have been extensively investigated for tumor treatment. However, the relationship between the composition of MPNs and the anti-tumor efficacy remains poorly defined. To address this issue, three MPNs were synthesized via a simple self-assembly approach using tannic acid (TA), bovine serum albumin (BSA), polyethylene glycol (PEG), and metal ions (such as Cu²⁺, Mn²⁺, and Ca²⁺). The resulting MPNs exhibited a hydrodynamic diameter of ~ 200&#xa0;nm, negative zeta potential, and favorable colloidal stability in biological media. Under tumor-mimicking microenvironmental conditions (low pH and/or high reactive oxygen species), both metal ions and polyphenols were rapidly released. In vitro assays demonstrated that all MPNs induced concentration- and time-dependent cytotoxicity in cancer cells. Biodistribution studies using Cy5-labeled TA-Cu and TA-Mn NPs confirmed preferential tumor accumulation. These MPNs exhibit potential in vivo antitumor effects. For example, after intravenous injection of TA-Mn NPs (20&#xa0;mg/kg), the tumor volume of 4T1 and Lewis lung cancer (LLC) mouse models was only 19.35% and 14.60% of the control group, respectively. Moreover, both Cu²⁺- and Mn²⁺-based MPNs extended survival in tumor-bearing mice without inducing observable systemic toxicity. In addition, no statistically significant difference in the anti-tumor efficacy was observed between Cu²⁺ and Mn²⁺-based MPNs. Collectively, this study establishes a foundational framework for the rational design of MPNs in synergistic cancer therapy, highlighting the critical role of metal ion selection in achieving potent, safe, and tunable nanotherapeutics.</p>