Haochen Yao

Tumor immunometabolism plays an important role in tumor progression and immune cell activity and is therefore critical to the efficacy of cancer immunotherapy. Modulation of immunometabolism to boost cancer immunotherapy is mostly based on targeting tumor cell metabolism, which often fails to address the tumor-promoting functions maintained by stromal cells. In contrast, targeting a metabolic checkpoint shared by tumor cells and cancer-associated fibroblasts (CAFs) can potentially overcome this limitation but has been relatively underexplored. Herein, a locally delivered, ultrasound activatable nanocatalytic platform is reported for immunometabolic cancer therapy. The platform is composed of sulfasalazine and a gallium-modified Fe-TCPP metal–organic framework nanozyme codelivered in an oxidized sodium alginate-based hydrogel. Ultrasound-activated gallium-modified Fe-TCPP boosts electron transfer, peroxide activation, and reactive oxygen species production while disrupting iron balance. Simultaneously, sulfasalazine inhibits SLC7A11-mediated cystine uptake in CAFs and tumor cells, reducing matrix remodeling and weakening the tumor’s antioxidant defense. This dual approach increases oxidative stress, reshapes the tumor microenvironment, induces immunogenic tumor cell death with ferroptotic traits, matures dendritic cells, and strengthens CD8+ T-cell responses. Consequently, it suppresses tumor growth in an immunocompetent osteosarcoma model and remains effective in a patient-derived OSCC xenograft model. Together, these findings demonstrate that targeting shared SLC7A11-mediated cystine dependence integrates stromal remodeling, tumor redox disruption, and antitumor immune activation.

Hepatocyte-like cells (HLCs) represent a promising therapeutic approach for acute liver failure (ALF), offering an alternative to primary hepatocytes, which are in short supply. Given the viscoelastic tissue properties of the liver and the growing recognition of the mechanical cues in physiology and disease, we investigated how ALF-induced changes in the liver's mechanical microenvironment might affect HLC-based cell therapy. Here, driven by specific disease-derived mechanical cues, we designed bioinspired hydrogel microspheres with tunable liver viscoelasticity to mimic the mechanical niche of healthy versus ALF liver tissue. We show that a fast-relaxation hydrogel niche mimicking the healthy liver guides the efficient differentiation of human adipose-derived mesenchymal stem cells (hADSCs) into functional HLCs by suppressing the formation of abnormal stress fibers and pathological YAP nuclear translocation through the ROCK axis. In both the carbon tetrachloride-induced and partial hepatectomy-induced ALF mouse models, these mechanically preconditioned HLCs exhibit significant therapeutic efficacy, promoting robust liver regeneration and acting as active mechanical regulators to suppress aberrant host mechanotransduction and remodel the diseased microenvironment. This disease mechanobiology-oriented strategy provides insights into the design of viscoelastic biomaterials for regenerative medicine and demonstrates a promising approach for enhancing cell therapy outcomes in liver failure.

Tumor starvation therapy is a promising metabolism‐targeting intervention, yet its efficacy is largely counteracted by lipid droplet (LD)‐driven compensatory metabolism in malignant cells. Existing LDs‐targeted approaches are further hampered by off‐target systemic metabolic disturbances and inherent immunosuppressive adverse effects. Here, we construct a zeolitic imidazolate framework‐8 (ZIF‐8)‐based nanomedicine loaded with 2‐deoxy‐D‐glucose (2‐DG) and surface‐decorated with copper‐tannic acid (Cu‐TA, ZIF‐8/2‐DG@Cu‐TA). This nanosystem reroutes intracellular LDs from tumor cells to adjacent cancer‐associated fibroblasts (CAFs) to realize synergistic tumor starvation and immunotherapy. In the acidic tumor microenvironment, the degradable Cu‐TA coating activates connexin 43 (Cx43) hemichannels on CAFs. After internalization by tumor cells, ZIF‐8/2‐DG releases 2‐DG to suppress glycolysis, while dissociated zinc ions disrupt mitochondrial bioenergetics and further trigger Cx43 hemichannels activation on tumor cells. Fully assembled Cx43 gap junctions mediate directional LDs trafficking from tumor cells to CAFs, restricting intracellular lipid energy pools sustaining malignant metabolic demands. Simultaneous blockade of glycolysis, mitochondrial respiration and lipid metabolism induces profound tumor‐cell metabolic collapse. The resulting metabolic stress strongly amplifies antitumor immunity and markedly suppresses both subcutaneous and orthotopic MOC1 tumors. Overall, this study establishes a gap‐junction‐driven triple metabolic starvation paradigm and offers mechanistic insights for next‐generation metabolic immunotherapies.

Castration-resistant prostate cancer (CRPC) remains lethal due to adaptive resistance mechanisms such as stress-induced autophagy and NF-κB survival signaling. Here, an injectable fiber-in-hydrogel depot is developed for sequential delivery of a multi-enzyme nanozyme (cobalt-epigallocatechin gallate coordination nanozyme, CoNZ) and the lysosomal inhibitor chloroquine (CQ). The preferentially released CoNZ catalytically generates reactive oxygen species, including hydroxyl radicals, and oxygen in situ, inflicting oxidative damage while relieving tumor hypoxia. Simultaneously, it depletes antioxidants (glutathione, NADPH) and impedes NF-κB nuclear translocation, priming CRPC cells for apoptosis. The subsequently released CQ impedes enzymatic degradation or cleavage in endolysosomes and autolysosomes and blocks TLR9/NF-κB signaling, preventing tumor cells from repairing damage or activating pro-survival pathways. In vitro and in vivo, this two-pronged approach synergistically overcomes CRPC's defenses, achieving markedly enhanced cancer cell apoptosis and ∼80% tumor suppression (with occasional complete regression), resulting in an approximately 10-fold reduction in final tumor volume compared to the untreated control, without systemic toxicity, far surpassing single or co-administered treatments. This work demonstrates a spatiotemporally orchestrated combination of nanocatalytic therapy and lysosomal inhibition that dismantles CRPC's resistance mechanisms, highlighting a broadly applicable paradigm for overcoming therapeutic resistance in aggressive cancers.

Chemo-immunotherapy is limited by the poor bioavailability, nonspecific distribution, and systemic toxicity of free drugs. Here, we develop a reactive oxygen species (ROS)-responsive prodrug strategy by conjugating paclitaxel (PTX) and the TLR7/8 agonist resiquimod (R848) with a phenylboronic ester (PBE) moiety to generate two ROS-activatable prodrugs, PTX–PBE and R848–PBE. These prodrugs spontaneously coassemble into carrier-free nanoparticles (PR NPs) with ultrahigh loading efficiency and tunable drug ratios. PBE modification improves systemic stability while enabling ROS-triggered drug release in the tumor microenvironment, allowing PTX-mediated immunogenic cell death and R848-mediated innate immune activation. In colorectal cancer models, PR NPs suppress tumor growth, reduce systemic toxicity, and remodel the tumor immune microenvironment by promoting antitumor immune responses. This prodrug engineering strategy provides a high-loading, activatable, and carrier-free platform for chemo-immunotherapy with potential for cancer treatment.

Triple‐negative breast cancer establishes a stromal‐metabolic barrier, characterized by dense fibrosis and metabolic dysregulation, to induce immunotherapy resistance. To dismantle this barrier, we propose a P rogrammable R ewiring of I mmuno‐ S tromal M etabolism ( PRISM ) strategy, supported by a POD‐like activity‐oriented machine learning (ML) screening of representative catalytic metals. A metabolic nanoregulator, Au@Fe–Co@HA (ACFH), was engineered to couple glucose starvation with Fe/Co‐mediated oxidative therapy. The Au core of ACFH acted as a glucose oxidase‐like enzyme to deplete glucose and generate endogenous H ₂ O ₂ , thereby powering the peroxidase‐like activity of the iron‐cobalt (Fe/Co) shell. In vivo, ACFH‐mediated combined therapy reduced GLUT1 expression in tumor tissues and suppressed glucose uptake and glycolysis‐associated metabolic activity. The GSH‐responsive release of Fe/Co ions disrupted redox homeostasis and activated immunogenic cell death (ICD), facilitating dendritic cell maturation, M1 macrophage polarization, and CD4 ⁺ /CD8 ⁺ T‐cell infiltration. When combined with immune checkpoint blockade, the therapeutic efficacy was further enhanced. In this study, ML was used to translate the therapeutic requirement for ROS‐amplified ferroptosis and immunogenic therapy into a quantifiable catalytic screening endpoint. By integrating this function‐oriented metal selection with the PRISM strategy, this work provides a rational nanoregulator design to overcome stromal‐metabolic resistance in TNBC.

The senescence of nucleus pulposus cells (NPCs) is a hallmark pathological feature of intervertebral disc degeneration. Senescent NPCs exhibit mitochondrial dysfunction and impaired mitophagy, thus compromising mitochondrial turnover and quality control. Current therapeutic strategies predominantly target external risk factors but do not restore mitophagy. In this study, a proline carbon dot‐composited poly(L‐methionine) (EG ₄₅ M ₂₅ /Pro‐CD) hydrogel is developed and employed to re‐establish the impaired mitophagy pathway. Expression levels of Parkin and phosphorylated Parkin increase, indicating successful activation of the mitophagy pathway. Restoration of mitochondrial function markedly reduces oxidative stress and the senescence‐associated secretory phenotype in NPCs. The levels of type II collagen and aggrecan recover to 84.63% and 77.31% of their normal ones, respectively. In an animal model, the administration of Pro‐CD in a thermo‐sensitive and injectable hydrogel effectively preserves the water content and height of intervertebral discs while maintaining the structural integrity and functional activity of NPCs. The mean Pfirrmann grade improves from 5.00 in the Control group to 3.33 after treatment, whereas the disc height index recovers to 82.06% of the physiological value. Collectively, our findings demonstrate that the EG ₄₅ M ₂₅ /Pro‐CD composite hydrogel has therapeutic potential to promote endogenous disc regeneration by enhancing mitophagy, re‐establishing redox homeostasis, and alleviating NPC senescence.

Tumor recurrence and metastasis following surgery remain major clinical challenges, largely due to residual lesions and immunosuppressive tumor microenvironment (TME). This work describes the development of a biodegradable hydrogel (PSR-Gel) based on oxidized sodium alginate and carboxymethyl chitosan co-loaded with R848 (a TLR7/8 agonist) and SR717 (a STING agonist) for localized postoperative immunotherapy. PSR-Gel exhibited a uniform porous structure, sustained drug release (~10 days), gradual in vivo degradation (~9 days), and excellent biocompatibility. In addition, it efficiently activated bone marrow-derived dendritic cells in vitro through a synergistic activation of the TLR7/8 and STING pathways. PSR-Gel used in a CT26 colon cancer model achieved a tumor suppression rate (TSR) of 94.33% with negligible toxicity, while remodeling the TME by modulating immune cell subsets. The combination treatment with αPD-L1 used in 4T1 breast cancer model resulted in a TSR of 97.87% and a cure rate of 83.33%, with survival exceeding 80 days. Moreover, PSR-Gel + αPD-L1 inhibited distant metastasis (TSR = 92.94% for secondary tumors) and prevented recurrence by inducing long-term immune memory, as evidenced by increased Tcm and Tem cell populations. Overall, this localized dual-agonist delivery system synergizes with immune checkpoint blockade to eliminate residual tumors, remodel the TME, and induce durable antitumor immunity, representing a promising and translatable strategy for postoperative cancer immunotherapy.