Biomaterial-enabled multimodal therapy for endometrial cancer: Subtype-guided immuno-metabolic modulation and...

Endometrial cancer (EC) encompasses various histological and molecular subtypes, each with unique immune, endocrine and metabolic characteristics, resulting in varying responses to treatment. Although immunotherapy, endocrine therapy and metabolic targeted therapy have broadened treatment options, the clinical efficacy varies due to subtype-specific drug resistance, systemic side effects, and the need for fertility preservation in young patients. This requires us to shift from simple combination therapy to a treatment model that integrates biological and subtype-specific information. The latest advancements in the field of biomaterials provide new approaches to achieve this integration. Tools such as nanocarriers and hydrogels can enable precise and localized drug delivery in the uterus, achieving controlled release based on specific tumor biological characteristics. For tumors with immune activity, they can locally deliver immune stimulants; for certain subtypes, they can directly provide continuous endocrine therapy within the tissue, avoiding systemic exposure. In cases of resistance, they can modify local metabolism to restore treatment sensitivity. Essentially, biomaterials act as intelligent interfaces, converting subtype-specific information into targeted treatment strategies. Specifically, biomaterial platforms can utilize endogenous tumor and tissue cues (pH, enzyme activity, redox state, or inflammatory signals) to trigger the on-demand release of immunomodulators, endocrine drugs, or metabolic regulators in the uterine microenvironment, thereby enhancing local efficacy while reducing systemic toxicity. Importantly, biomaterial-enabled strategies extend beyond tumor control by incorporating endometrial repair and regeneration into therapeutic design. By temporally decoupling antitumor intervention from regenerative signaling within a single platform, these approaches directly address the fertility-preserving imperative of EC management. This review systematically presents new multimodal therapeutic strategies for EC made possible by biomaterials, focusing on how spatial, temporal and biological programmability enables subtyped treatment, immunometabolic reprogramming and integrated regeneration. We explore design principles, translational challenges and clinical implications, proposing biomaterials as a paradigm for precision therapy focused on fertility preservation. It is important to note that this review systematically positions endometrial regeneration focused on preserving fertility as a fundamental therapeutic principle rather than as a complement downstream of tumor control, advocating its integration into comprehensive treatment plans from the start of subtyp-targeted therapy.