In situ forming hydrogels for colorectal cancer therapy

In situ forming hydrogels (ISFGs) have emerged as a promising platform for localized drug delivery in colorectal cancer (CRC) therapy, addressing limitations of systemic treatments such as off-target toxicity and poor drug accumulation at tumor sites. These hydrogels undergo sol-gel transitions in response to stimuli (e.g., temperature, pH, redox) to form drug-laden depots within the tumor microenvironment or at the surgical bed. This review outlines recent advances in ISFG materials-including thermosensitive poloxamers, ion-responsive alginates, Schiff-base dynamic networks, and ROS/pH-sensitive polymers-highlighting their injectability, adhesiveness, and biocompatibility. Therapeutically, ISFGs have been successfully engineered to deliver cytotoxic agents, immunomodulators, photosensitizers, and metabolic inhibitors, enabling synergistic chemo-immunotherapy, postoperative cancer vaccines, and tumor microenvironment remodeling. Preclinical studies have demonstrated enhanced antitumor efficacy, reduced recurrence, immune activation, and even systemic abscopal effects, with minimal systemic toxicity. Clinical translation is advancing, with some ISFG systems entering early-phase trials. This review emphasizes ISFGs' unique capacity to combine spatially confined treatment with systemic immune priming, making them ideal for neoadjuvant, adjuvant, or interventional CRC therapy. Future directions include personalized hydrogel-vaccine platforms, multimodal integration (e.g., ablation + immunotherapy), and smart hydrogels tailored to CRC biology. ISFGs thus represent a versatile and translationally promising strategy for improving local tumor control and long-term outcomes in colorectal cancer.