Metal ion-amplified phototherapy for tumors: Mechanisms, nanomaterial design, and synergistic strategies

Cancer remains a major threat to the health of human for its high incidences and mortality. Traditional treatment methods, such as surgery, radiotherapy and chemotherapy, are often limited by serious side effects and insufficient curative effect. Phototherapy, including photodynamic therapy (PDT) and photothermal therapy (PTT), has become a promising alternative therapy. Although PDT and PTT exhibit intrinsic tumor selectivity, collateral damage to surrounding normal tissues may PDT has strong tumor selectivity still occur under certain conditions, particularly due to light scattering, heat diffusion, or off-target photosensitizer accumulation. Recent progress suggests that metal ion-dependent cell death (MIDCD), including ferroptosis, cuproptosis, and others, can be strategically integrated with phototherapy to partially mitigate these limitations or provide alternative therapeutic routes under challenging tumor microenvironmental conditions. This review systematically discusses the mechanisms and synergistic effects of the combination of PDT/PTT and metal ion interference therapies, which emphasizes the roles of iron, copper, calcium, zinc, magnesium and manganese in enhancing the treatment efficacy. We also summarize the design of metal-based nanomaterials and inducers, which made the spatiotemporal controlled ion release and multimodal therapy synergistic. Finally, we discuss the challenges of clinical transformation and future directions, and emphasized the potential of metal ion amplified phototherapy as an effective strategy for accurate cancer treatment.