Sustainable hydrogel platforms for local tumor therapy: From rational design to clinical translation

Locoregional cancer therapy has emerged as a transformative strategy to address the inherent limitations of systemic administration, including off-target toxicity and inadequate intratumoral drug accumulation. Sustainable hydrogels—defined herein as hydrogel systems derived from renewable or biocompatible polymers that exhibit biodegradability, minimize systemic toxicity and drug waste, provide durable therapeutic effects, and preferably originate from natural or sustainably sourced materials—have revolutionized local tumor treatment by enabling controlled and sustained drug release directly at tumor sites or within postsurgical cavities. This review provides a comprehensive overview of recent advances in hydrogel-based platforms for local cancer therapy, with emphasis on rational material design principles, stimuli-responsive drug delivery strategies, and clinical translation progress. Stimuli-responsive hydrogels that leverage tumor microenvironment cues—including acidic pH, temperature gradients, matrix metalloproteinase overexpression, and reactive oxygen species—achieve spatiotemporally controlled drug release, enhancing therapeutic efficacy while minimizing systemic exposure. The integration of nanomedicine with hydrogel networks through nano-in-micro technologies enables sequential delivery of chemotherapeutic agents, immune checkpoint inhibitors, and antiangiogenic drugs, creating synergistic combination therapies. Notably, the FDA approval of UGN-102 (mitomycin-containing thermogel) for low-grade intermediate-risk non-muscle-invasive bladder cancer in June 2025 represents a landmark achievement validating hydrogel-based local therapy. Emerging applications that remain preclinical include postoperative immunotherapy to prevent recurrence, induction of tertiary lymphoid structures, NK cell delivery, and 3D-printed personalized hydrogel implants, none of which have yet advanced to clinical evaluation. Key challenges remain in optimizing drug release kinetics, establishing standardized characterization methods, navigating regulatory pathways, and identifying predictive biomarkers for patient stratification. This review provides a comprehensive overview of the current landscape and future directions for sustainable hydrogels in precision oncology.