Cancer remains a leading cause of death globally, and despite progress in surgery, chemotherapy, radiotherapy, and immunotherapy, treatment efficacy and safety are often constrained. A principal barrier to durable responses is the local ecosystem surrounding tumors, commonly termed the tumor microenvironment (TME). The TME can antagonize therapies by limiting drug distribution, sustaining immunosuppression, and preventing effective anti-tumor immune responses. This review focuses on hydrogel-based drug delivery approaches designed to modulate the TME and thereby improve anti-tumor treatment outcomes, with emphasis on applications in tumor immunotherapy.
The TME comprises a complex network of cancer cells, stromal cells, extracellular matrix, vasculature, and infiltrating immune cells. Its physical and immunological characteristics—such as dense extracellular matrix, hypoxia, abnormal vasculature, and suppressive immune cell populations—can impede drug penetration, promote resistance, and blunt immune-mediated tumor clearance. Clinically relevant tumor phenotypes are often classified by immune contexture: hot tumors (inflamed, with immune infiltration) are generally more responsive to immunotherapy, whereas cold tumors (non-inflamed) frequently resist immune-based strategies. Cold tumors can be further described by immune-desert and immune-excluded patterns, each presenting distinct barriers to immune activation and infiltration.
Hydrogels are water-swollen, crosslinked polymer networks that can be engineered across a range of mechanical and structural parameters. Key features that make hydrogels attractive for TME modulation include their tunable microstructures, capacity to carry and release high payloads of therapeutic agents, and amenability to scalable manufacturing. Hydrogels can be formulated for local implantation, injectable administration, or as depot systems that provide sustained, localized release. Because they can host multiple agents and be engineered to respond to environmental cues, hydrogels offer opportunities to tailor local pharmacokinetics and coordinate combinations of treatments to address the multifaceted challenges posed by the TME.
In tumors that already exhibit immune infiltration (hot tumors), hydrogel-based approaches aim to amplify and sustain anti-tumor immunity while minimizing systemic toxicity. Localized hydrogel delivery can concentrate immune stimulatory agents, cytokines, adjuvants, or checkpoint modulators within the tumor bed to boost existing immune responses. By providing controlled release and a local reservoir of therapeutic molecules, hydrogels can prolong immune activation, promote effector cell function, and potentially reduce off-target adverse effects associated with systemic administration.
Cold tumors require strategies to recruit and activate immune effectors and to reverse local immunosuppression. The review discusses hydrogel-dependent tactics tailored to two cold-tumor phenotypes. For immune-desert tumors, approaches focus on delivering chemoattractants, antigenic material, or agents that promote dendritic cell recruitment and priming to initiate an immune response. For immune-excluded tumors—where immune cells accumulate at the tumor margin but fail to infiltrate—hydrogels can be used to deliver matrix-modifying enzymes, modulators of stromal barriers, or agents that normalize vasculature to facilitate immune cell penetration. In both contexts, hydrogels serve as platforms for localized, multimodal interventions designed to convert cold tumors into inflamed, therapy-responsive states.
Hydrogel-based interventions alter TME biology through multiple immunological mechanisms. Localized release profiles enable sustained stimulation of antigen-presenting cells, enhanced recruitment of effector T cells, and modulation of suppressive cell populations. Hydrogels can change local cytokine gradients, present antigens or adjuvants in depot form, and reduce systemic exposure to immunomodulators. By reshaping immune cell trafficking and activity within the tumor milieu, these materials can potentiate the mechanisms underpinning successful immunotherapy.
Despite promising conceptual advantages, hydrogel-dependent TME modulation faces translational hurdles. Key challenges include demonstrating safety and efficacy in clinically relevant models, scalable and reproducible manufacturing, regulatory considerations for combination products, and integration with existing therapeutic workflows. Further work is needed to define optimal material properties, dosing strategies, and combinations of agents for specific tumor phenotypes. The review highlights the need for coordinated efforts to address these barriers and to advance hydrogel platforms from preclinical testing toward clinical translation.
Hydrogels represent a versatile and scalable class of drug delivery systems with strong potential to remodel the tumor microenvironment and improve outcomes of anti-tumor therapies, especially immunotherapy. Their tunable structures, high loading capacity, and capacity for localized, sustained, and combinatorial delivery position hydrogels as promising tools to convert cold tumors into hot tumors, overcome local immunosuppression, and coordinate multimodal treatment strategies. The field must still confront significant translational and manufacturing challenges to realize the clinical promise of these approaches.