A Biologically Inert Tamoxifen-Derived Long-Lasting Hydrogel-Mediated Immunochemotherapy Can Mitigate Tumor Progression and Activate T Cell Immunity

The immunosuppressive tumour microenvironment (TME) is often regarded as the Achilles heel of cancer therapy, as it can limit immune cell infiltration and therapeutic efficacy. To address this, we engineered a long-lasting tetrapeptide-conjugated lithocholic acid-tamoxifen-derived injectable hydrogel (LTG4-Gel) that, upon implantation, does not exert any systemic toxicity in mice, rats and rabbits. LTG4-Gel retained its injectability and rheological flow properties even after the entrapment of multiple drugs, as confirmed by rheology, UV absorption, circular dichroism and atomic force microscopy. Doxorubicin (DOX) entrapped hydrogel (DOX-Gel) significantly induced the anti-tumour responses with enhanced survival in different syngeneic murine tumour models. We further showed that the engineered chimeric gel, upon entrapment of DOX and an immune agonist (c-di-GMP sodium salt (GMP)) (DOX-GMP-Gel), targeting the STING (stimulator of interferon gene) pathway, effectively mitigates tumour progression and increases survival across different tumour models. We demonstrated that DOX-GMP-Gel therapy activates the antitumour T cell immunity and generates a memory response to clear distant tumours. Our study provides a systemic design of long-lasting low molecular hydrogel to deliver the combination of immunostimulatory adjuvants and immunogenic cell death-inducing agents, offering a promising approach to modulate the tumour microenvironment for enhanced cancer therapy.