Stimuli-responsive hydrogels have advanced from inert carriers to programmable interfaces that transduce pathological cues into precisely localized therapy across the tumor margin draining lymph node axis. This review synthesizes polymer chemistry, transport physics, and tumor immunology to derive design principles for injectable depots that couple microenvironment selective inputs (acidity, reactive oxygen species, proteolysis) with network architecture, viscoelasticity, adhesivity, and poroelastic transport to enforce spatiotemporally resolved presentation of chemotherapeutics, antibodies, cytokines/adjuvants, vaccines, and cellular agents. We relate quantitative release descriptors, diffusion- versus erosion-dominated regimes, stimulus – response gain, and mesh size – affinity coupling to immune outputs including antigen-presenting cell maturation, CD8+ infiltration, tissue-resident memory persistence, and myeloid reprogramming, and we formalize depots as stimulus-modulated diffusion – erosion reactors. We further systematize architectural primitives (natural and synthetic matrices, interpenetrating networks, and composite depots integrating micelles, liposomes, and nanocages) that enable order-controlled combination regimens. Translational considerations are framed within a quality by design logic (critical quality attributes and process parameters, sterilization and stability windows, syringeability) alongside placement heuristics for defined anatomic use cases (resection cavities, serosal surfaces, nodal basins) and safety-by-design tactics that bound burst release and off-target inflammation. Finally, we outline physics- and data-informed toolkits, finite element transport, poroelastic mechanics, and surrogate modeling to compress design cycles and de-risk GMP (good manufacturing practice) scale-up. Collectively, these elements motivate a staged roadmap that aligns material specification with clinical workflows and biomarker-anchored trials, positioning injectable hydrogels as a reproducible platform for precise, durable, and scalable cancer immunotherapy.
Kaveh et al. (Wed,) studied this question.