Intratumoral Lactate Depletion Based on Injectable Nanoparticles−Hydrogel Composite System Synergizes with Immunotherapy against Postablative Hepatocellular Carcinoma Recurrence

Abstract

Thermal ablation is a crucial therapeutic modality for hepatocellular carcinoma (HCC), but its efficacy is often hindered by the high recurrence rate attributed to insufficient ablation. Furthermore, the residual tumors following insufficient ablation exhibit a more pronounced immunosuppressive state, which accelerates the disease progression and leads to immune checkpoint blockade (ICB) resistance. Herein, we present evidence that heightened intratumoral lactate accumulation, stemming from the augmented glycolytic activity of post‐ablative residual HCC cells, may serve as a crucial driving force in exacerbating the immunosuppressive state of the tumor microenvironment (TME). To address this, we design an injectable nanoparticles‐hydrogel composite system (LOX‐MnO2@Gel) that gradually releases lactate oxidase (LOX)‐loaded hollow mesoporous MnO2 nanoparticles at the tumor site to continuously deplete intratumoral lactate via a cascade catalytic reaction. Using subcutaneous and orthotopic HCC tumor‐bearing mouse models, we confirm that LOX‐MnO2@Gel‐mediated local lactate depletion could transform the immunosuppressive post‐ablative TME into an immunocompetent one and synergizes with ICB therapy to significantly inhibit residual HCC growth and lung metastasis, thereby prolonging the survival of mice post‐ablation. Our work proposes an appealing strategy for synergistically combining anti‐tumor metabolic therapy with immunotherapy to combat post‐ablative HCC recurrence.This article is protected by copyright. All rights reserved

Hydrogel Composites for Multifunctional Biomedical Applications

“…These materials can respond to changes in the environment, enabling the controlled release of drugs or active agents in response to specific physiological conditions. Innovative combinations of materials, such as injectable nanoparticle-hydrogel systems and micelle-hydrogel composites [26,66], suggest a move toward more complex, multifunctional systems. This indicates a demand for therapies that can be administered directly to the site of injury or disease, highlighting the continued development of injectable hydrogel systems [23,26,27].…”

“…Innovative combinations of materials, such as injectable nanoparticle-hydrogel systems and micelle-hydrogel composites [26,66], suggest a move toward more complex, multifunctional systems. This indicates a demand for therapies that can be administered directly to the site of injury or disease, highlighting the continued development of injectable hydrogel systems [23,26,27]. The integration of nanotechnology, through the inclusion of nanoparticles and nanozymes [64,[67][68][69], plays a critical role in enhancing the functionality of hydrogel composites, particularly for targeted drug delivery and antibacterial applications.…”

“…An injectable nanoparticle-hydrogel composite system aims to deplete intratumoral lactate in combination with immunotherapy against hepatocellular carcinoma recurrence. This system slowly releases lactate oxidase-loaded hollow mesoporous MnO 2 nanoparticles, transforming the immunosuppressive tumor environment into an immunocompetent setting [26]. Moreover, a graphene oxide/chitosan injectable composite hydrogel has been prepared for the controlled release of doxorubicin, optimizing local bioavailability for the treatment of solid tumors [27].…”

“…Targeted and controlled drug delivery techniques strive for localized, precise therapies that minimize systemic exposure and side effects. This includes developing topical delivery systems for nitric oxide [25] and injectable nanoparticle-hydrogel composites for liver cancer treatment [26], along with graphene oxide/chitosan hydrogels for targeted chemotherapy delivery [27].…”

Role of lactate and lactate metabolism in liver diseases (Review)

“…It reverses the immunosuppression in TME by inhibiting MDSCs and Tregs while activating NK cells and DCs ( 128 ). Another study used nanotechnology to construct a nanoparticle-hydrogel composite system, LOX-MnO2@Gel; this system depletes lactate from the TME through a cascade catalytic reaction, then restores intratumoral cytotoxic T lymphocyte function, reduces the ratio of Tregs/M2-like macrophages, enhances antitumor immune responses and transforms the immunosuppressive TME into an immunocompetent one ( 129 ). This approach markedly inhibits residual tumor growth, suppresses lung metastasis and prolongs mouse survival in subcutaneous and in situ HCC mouse models ( 129 ).…”