Hydrogen sulfide in cancer therapy: Intelligent delivery platforms and synergistic therapeutic paradigms

Hydrogen sulfide (H₂S) has emerged as a pivotal gaseous signaling molecule in cancer therapy, demonstrating unique dose-dependent therapeutic effects that have established new paradigms for gas-mediated treatments. To enable precise H₂S delivery in cancer therapy, various H₂S donor compounds have been developed, and a range of intelligent delivery systems have been subsequently designed. These systems are capable of specifically accumulating at tumor sites and can release H₂S in a controlled and responsive manner within the tumor microenvironment (TME). This comprehensive review systematically examines the fundamental physicochemical properties and multifaceted biological functions of H₂S while providing a detailed classification of H₂S donors into inorganic and organic categories. We further classify existing H₂S delivery strategies into endogenous-responsive systems (e.g., pH-, GSH-, and enzyme-triggered systems) and exogenous-responsive approaches (e.g., light-, ultrasound-, and electric field-activated methods), supported by representative case studies. Above all, this review highlights the remarkable potential of H₂S in enhancing various therapeutic modalities, including radiotherapy, chemotherapy, thermotherapy, catalytic therapy, and immunotherapy, primarily through its regulatory effects on heat shock protein expression, catalase activity modulation, and profound TME remodeling, which provides valuable insights for designing next-generation H₂S delivery systems and their combinatorial applications in cancer treatments.