Beyond Apoptosis: Platinum Phototherapeutics Overcome Resistance by Triggering Diverse Cell Death Pathways

Abstract

Platinum(Pt)-based drugs remain the cornerstone of malignant tumor treatment, but are severely constrained by drug resistance. Conventional Pt agents primarily induce apoptosis, yet resistant cancer cells can bypass this pathway, leading to treatment failure. In contrast, phototherapeutic Pt complexes, leveraging photodynamic therapy and photoactivated chemotherapy, represent a novel approach to overcoming resistance by either enhancing apoptosis or activating alternative programmed cell death (PCD) pathways. This review provides a comprehensive overview of Pt-based photosensitizers and photoactivated agents that trigger diverse PCD pathways, including apoptosis, autophagy, ferroptosis, pyroptosis, and immunogenic cell death, to combat resistance. We elucidate the unique features and mechanistic underpinnings of each pathway, providing in-depth analyses of representative complexes to illustrate their PCD induction strategies and effectiveness in reducing resistance. Additionally, we present critical insights and forward-looking perspectives on the development of next-generation Pt phototherapeutics that leverage diverse PCD pathways. Overall, this review highlights the significance of multimodal PCD induction, proposing that targeting these pathways offers a novel strategic opportunity for Pt-based anticancer agents to overcome drug resistance.