The pathological progression of dry eye disease (DED) involves a vicious cycle of oxidative stress and inflammation, posing a critical therapeutic challenge. Conventional therapies, such as cyclosporine A (CsA), are limited by poor corneal permeability and low ocular bioavailability. Here, we developed a novel, biocompatible nano-eye drop formulation using Chrysanthemum indicum L.-derived extracellular vesicles (CELNs) as a natural nanocarrier to engineer CsA-loaded CELNs (CsA@CELNs) for synergistic DED therapy. By combining CsA-mediated immunoregulation with enhanced corneal permeability and the intrinsic antioxidant and anti-inflammatory activities of CELN, the CsA@CELNs effectively disrupts the core pathogenic feedback loop of DED. In vitro and in vivo data demonstrated that a one-week, twice daily topical treatment with CsA@CELNs alleviated oxidative stress by scavenging reactive oxygen species (ROS) and activating the Nrf2/HO-1/NQO1 signaling pathway, while concurrently suppressing inflammation through inhibiting the NF-κB pathway and promoting macrophage repolarization from the pro-inflammatory M1 to the anti-inflammatory M2 phenotype. In a murine DED model, CsA@CELNs eye drop significantly restored tear secretion, promoted regeneration of corneal and conjunctival cells, and improved lacrimal gland histology. This multi-targeting CsA@CELNs system not only provides a safe and effective nanotherapeutic strategy for DED but also establishes plant-derived extracellular vesicles as a promising drug delivery platform for treating ocular surface and other inflammatory diseases.

Oral nano-vaccines offer a non-invasive approach for cancer immunotherapy by combining gastrointestinal delivery with mucosal immune induction and systemic antitumor immune activation. However, their development remains constrained by antigen degradation in the gastrointestinal tract, mucus entrapment, inefficient M-cell and antigen-presenting cell uptake, mucosal immune tolerance, limited intracellular antigen processing, and interindividual variation in the gut microbiota. In this Review, we propose the “Oral-GALT-Tumor Immune Axis” as a conceptual framework for organizing current evidence on how orally delivered nanovaccines may connect intestinal antigen transport, gut-associated lymphoid tissue (GALT)-mediated immune priming, systemic immune trafficking, and tumor microenvironment modulation. By placing gastrointestinal barriers and GALT activation upstream of distant antitumor immunity, this framework extends conventional discussions of oral vaccination and the cancer-immunity cycle toward the design of oral cancer nanovaccines. We summarize major oral delivery barriers and discuss how lipid-based, polymeric, biomimetic, stimuli-responsive, receptor-targeted, and nanoadjuvant-based platforms may improve antigen protection, intestinal transport, immune-cell targeting, and antigen presentation. We further review protein and nucleic acid-based antigen processing, CD4⁺ and CD8⁺ T-cell activation, humoral responses, macrophage polarization, myeloid-derived suppressor cell modulation, and microbiota-associated immune regulation. Emerging directions, including oral mRNA delivery, virus-like and biomimetic platforms, microbiota-integrated nanomedicines, artificial intelligence-assisted design, and combination with immune checkpoint blockade, are also discussed. Finally, we highlight unresolved challenges in delivery efficiency, oral tolerance, microbiota variability, long-term safety, immune readout standardization, manufacturability, and clinical translation. Together, these discussions outline both the promise and current limitations of oral nanovaccines and may help guide the rational design and translational evaluation of next-generation cancer immunotherapy platforms.

The Active Transport and Retention (ATR) principle offers a new strategy to enhance tumor entry of nanodrugs via transcytosis. However, its application is limited by poor tumor-homing, endothelial polarized efflux, and uncontrollable transcytosis of the nanodrug. Herein, we construct a bio-mimetic micro-nano system (PG@BAM-LRC) comprising nanoliposomes (LRC) and berbamine (BAM) within platelet-derived microcarrier (PG), leveraging PG's tumor-homing ability and MMP-9 responsive remodeling for tumor-specific cargo release. Thereafter, BAM selectively promotes basal transendothelial transport of LRC toward the tumor by modulating apical recycling endosomes. While R8 promotes the cellular uptake, the arginine-lysine-lysine-arginine-cysteine (Cys) ligand facilitates Golgi-targeted transendothelial transport of LRC, bypassing the endo-lysosome pathway. Once inside tumor cells, furin-mediated Cys-cleavage halts transcytosis, yielding superior intracellular drug retention compared to the non-cleavable Cys counterpart (LRC'). Four murine tumor models are established, demonstrating high heterogeneity in collagen density, vascularity, and EPR effects. An orthotopic pancreatic tumor, characterized by minimal EPR effect, is selected to demonstrate the ATR effect of PG@BAM-LRC. PG@BAM-LRC loaded with BAY-872243 exhibits exceptional tumor accumulation and therapeutic outcome compared to LRC, PG@LRC without BAM, and PG@BAM-LRC. Collectively, this study establishes PG@BAM-LRC as a robust tumor-targeting system leveraging the ATR mechanism while addressing tumor heterogeneity.

Nanodrug delivery systems (NDDSs) offer distinctive advantages in tumor immunotherapy, not only by enhancing drug distribution, targeting, and bioavailability but also by actively engaging in immune regulation through multiple mechanisms. In recent years, researchers have increasingly recognized that the NDDS itself can act as a pivotal driver in immune activation, participating in the induction of immunogenic cell death (ICD), the activation of dendritic cells (DCs) and T cells, the reprogramming of immunosuppressive cell populations, and the remodeling of the tumor immune microenvironment (TIME). Various nanomaterial platforms are undergoing a functional transition from "drug carriers" to "immune amplifiers." These systems are capable of spatiotemporally orchestrating synergistic responses between innate and adaptive immunity or directly modulating immune cells through specific signaling pathways to establish durable immune memory. This review systematically summarizes the key design principles and immune-activating mechanisms of diverse nanocarriers, and discusses their prospective applications in immunotherapy, particularly in combination with other therapeutic modalities. Emerging approaches, including AI-driven strategies, as well as current challenges are also highlighted. The work aims to provide theoretical foundations and design insights for the development of intelligent, immune-driven NDDSs that can advance the next generation of precision cancer immunotherapy.

Immune checkpoint blockade, exemplified by anti-PD-L1 antibody (αPD-L1), has revolutionized cancer immunotherapy. Nevertheless, its therapeutic potential is constrained by the inherently low tumor immunogenicity and the persistence of cancer stem cells (CSCs), which drive immune escape and tumor recurrence. Here, a CSC-targeted, pH-sensitive liposomal nano-cocktail of doxorubicin and bufalin (PSLB/D), was demonstrated to elicit robust immunogenic cell death (ICD), thereby potentiating the efficacy of αPD-L1 in immunologically 'cold' triple-negative breast cancer (TNBC) models. The PSLB/D itself demonstrated potent synergistic tumor-inhibitory effects in both cell lines and 3-D tumor spheroids, and effectively eliminated CSCs, with 85-90% reductions in both primary and secondary sphere formation. Deep penetration and robust ICD-mediated immune response were observed in patient-derived organoids, highlighting its translational potential. The therapeutic efficacy was validated in immunocompromised MDA-MB-231 and immunocompetent 4T1 orthotopic mouse models. Notably, in immunocompetent 4T1 models, PSLB/D induced strong expression of calreticulin, leading to the recruitment of dendritic cells and cytotoxic CD8⁺ T cells. Activation of these immune cells converted the immunosuppressive 'cold' tumors into immunogenic 'hot' ones, substantially amplifying the effectiveness of αPD-L1. This chemo-immunotherapy also generated memory T cells, suggesting the potential for longer antitumor immune responses. STATEMENT OF SIGNIFICANCE: Cancer recurrence and immune evasion in triple-negative breast cancer (TNBC) are largely driven by resilient cancer stem cells (CSCs). This study introduces a pH-sensitive liposomal nano-cocktail composed of doxorubicin and a CSC inhibitor, specifically engineered to overcome the immunosuppressive tumor microenvironment. We demonstrate that this nanococktail triggers potent immunogenic cell death (ICD) in patient-derived organoids and orthotopic models, exceeding the efficacy of conventional formulations or monotherapy. By successfully converting "cold" TNBC tumors into immunologically "hot", the nano-cocktail significantly amplifies anti-PD-L1 immunotherapy outcomes. These findings offer a compelling evidence-based framework for integrating targeted nanomedicine with clinical chemo-immunotherapy protocols to prevent recurrence.

Tumor antigen heterogeneity and T cell inhibition limit the efficacy of chimeric antigen receptor T (CAR-T) cells in solid tumors. Here, we engineered synthetic M13 bacteriophage-based bispecific engagers (BiPEs) that enable CAR-T cells to recognize multiple antigens and resist dysfunction, thus mediating broad and durable clearance of tumors. Specifically, BiPEs simultaneously conjugate single-chain antibodies against distinct tumor targets on phage pIII proteins via SpyTag-SpyCatcher. These engagers redirect M13 phage-specific CAR-T (MCAR-T) cells to eliminate heterogeneous tumor subclones and ignite immunity to remodel CAR-T function. In syngeneic glioblastoma models, BiPEs enhanced MCAR-T efficacy against antigenically diverse tumor cells, prolonging survival time significantly compared with single-target CAR-T. Critically, lipid nanoparticle-delivered MCAR mRNA generated functional CAR-T cells in vivo with effective multitargeting activity. In sum, this modular platform overcomes antigenic heterogeneity and T cell inhibition through programmable multitarget recognition, providing a scalable strategy for CAR therapy in solid tumors.

Liposomal nanoparticulate drug delivery systems (LNDDSs) are clinically validated nanomedicine platforms seeing regular use in oncology and infectious disease. Their applications have rapidly expanded with several tissue targeting formulations in early-phase clinical trials. Beyond small molecular drugs, LNDDSs are increasingly employed for delivery of nucleic acid therapeutics, such as ribonucleic acid (RNA) based vaccines and immunomodulators. Recent advances in nanomaterials have enabled LNDDSs not only to transport therapeutic agents across systemic biological barriers but also to selectively destabilize plasma and organelle membranes, such as endosomes and mitochondria, addressing a wide range of diseases. This review systematically examines design strategies for LNDDSs that traverse key biological barriers focusing on the blood-tumor barrier, blood-brain barrier, and lymphatic transport barriers. We further explore approaches including fusogenic, pH-, redox- and, enzyme-sensitive and externally (ultrasound and thermal) triggered LNDDSs to facilitate internalization and membrane destabilization for specific organelle-targeting. The mechanisms and representative formulations and of membrane interactions, and clinical progress are discussed. Finally, the translational opportunities and challenges, and future perspectives for rational design of next-generation LNDDSs are addressed.

Current immunotherapy for melanoma remains limited by low immunogenicity, immune-related toxicity, and an immunosuppressive tumor microenvironment (TME), necessitating more effective strategies to enhance treatment outcomes. Enhancing immunogenic cell death (ICD) induction with immune remodelling offers a promising approach to boost antitumor immunity. Here, we develop a transdermal microneedle (MN) system co-delivering garlic-derived nanovesicles (Ve) and immunomodulatory garlic polysaccharides (GP) to synergistically activate a self-reinforcing cell death pathway and reprogram the immunosuppressive TME. The dissolving MN platform enables efficient intratumoral delivery of Ve-fused thermosensitive liposomes (TSVL@PTX/ICG), loaded with paclitaxel (PTX) and the photosensitizer indocyanine green (ICG). Upon near-infrared (NIR) irradiation, ICG-mediated photothermal heating triggers rapid drug release, inducing pyroptosis via gasdermin E (GSDME) cleavage while amplifying photodynamic therapy (PDT)-driven mitochondrial damage. This dual cell death mechanism elicits robust ICD, releasing tumor antigens and damage-associated molecular patterns (DAMPs) to enhance dendritic cell activation and cytotoxic T-cell infiltration. Concurrently, GP reprograms tumor-associated macrophages (TAMs) from immunosuppressive M2 to pro-inflammatory M1 phenotypes, reshaping the TME into an immunostimulatory niche. This multi-modal approach, combining pyroptosis-driven ICD, PDT, and immune remodelling achieves potent antitumor immunity and melanoma suppression, highlighting the potential of plant-derived therapeutics in cancer immunotherapy. (c) 2026 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.

In this study, biodegradable controlled-release anti-Phytophthora granules were prepared using poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) as the polymer matrix and cinnamic acid (CA) as the active compound by the extrusion spheronization method. Two formulations were made with poly(vinylpyrrolidone) (PVP) and poly(vinyl alcohol) (PVA) as the binder, respectively. The size of the granules falls between 2.0 and 0.5 mm. The thermal stability of the formulations was verified using differential scanning calorimetry and thermogravimetric analysis. Combined with Fourier transform infrared spectroscopy, no new functional group was observed, indicating that no chemical interaction was present between the starting materials in the formulations. Release kinetics of the formulations in water and soil were studied and fitted to the Higuchi model, suggesting a Fickian diffusion mechanism governed the drug release. Both formulations show in vitro anti-Phytophthora activity, and the Gompertz equation was used to estimate and describe Phytophthora inhibition. Both formulations achieved over 50% inhibition over 21 days.

Cancer stem cells (CSCs) are intrinsically resistant to conventional therapies and play a pivotal role in cancer metastasis and recurrence. Eradication of CSCs requires combination strategies that simultaneously target multiple pathways at therapeutical concentrations throughout tumours. This study investigated the potential of a fusogenic pH-sensitive liposomal (pSL) nanococktail comprising doxorubicin and bufalin for targeting CSCs in clinically relevant HER2-positive breast cancer models, including cell lines (CD44high HCC1954 and CD44low BT474), homotypic and heterotypic spheroids, patient-derived organoids, and orthotopic HCC1954 mouse xenografts. At the optimal doxorubicin: bufalin ratio (10:1), the pSL-cocktail demonstrated pronounced synergistic efficacy and significantly outperformed all control formulations, including monodrug-loaded pSLs, non-pH-sensitive (DOXIL-like) liposomes, and free drugs. It significantly suppressed tumour proliferation and stemness, including CSC-associated migration, mammosphere formation, and self-renewal. In spheroids, the nanococktail rapidly penetrated to the spheroid core (≥100 µm within 1 h) and suppressed invasive dissemination. Similarly, it disrupted patient-derived organoids, achieving > 90% reduction in ATP levels and > 90% cell death. In vivo, the pSL-cocktail was well-tolerated and achieved significant tumour shrinkage, whereas DOXIL-like liposomes and free drugs showed minimal activity or severe adverse effects. Overall, this pSL-cocktail demonstrates strong potential for CSC-elimination and tumour clearance through synergistic drug combination, superior tumour penetration, and endosomal pH-triggered intracellular drug release.

Carrier-based systems, particularly liposomes, continue to be widely investigated for delivering anticancer treatments. In recent years, multiple approaches have been explored to achieve on-demand delivery of therapeutic cargo from these systems. Here, ultrasound has come to the fore as a practical and precise stimulus to trigger drug release from various formulations. This review explores the interplay between ultrasound and different micro and nanocarriers in oncology, highlighting the mechanisms of ultrasound-triggered delivery, relevance of carrier composition and particle size, cancer types in which the technique holds the most promise, and current barriers and future opportunities related to this approach. We also summarize the existing preclinical studies of US-responsive carriers, with a focus on lipid-based delivery systems. Through the review, the clinical translatability of high-intensity focused ultrasound in drug delivery platform designs is showcased.

Oral liposome drug delivery system has gained attention due to their potential to improve patient compliance, enhance the bioavailability of encapsulated poorly soluble drugs, and protect drugs from gastrointestinal degradation. Liposomes structurally mimic the human cell membrane, and so are biocompatible and facilitate interactions with cell membranes. However, liposome drug delivery remains inherently challenging due to limitations such as physicochemical instability, limited permeability across GI barriers, and manufacturing scalability constraints. This review first summarizes the current innovative oral liposome products such as Meriva®, Lipicur, and silymarin liposomes. This is followed by a comprehensive overview of the biological barriers for liposome absorption. The report further reviews current understanding the mechanisms for liposomes to cross the GI track and enter the bloodstream, including cellular uptake, transepithelial transport, and lymphatic transport. Formulation strategies to improve absorption such as lipid composition, surface modification techniques such as PEGylation and chitosan are discussed. Understanding these properties is essential for enhancing transepithelial transport efficiency and designing effective oral liposome delivery systems. Finally, the recent development in manufacturing scalability is also covered. Owing to their favorable properties, oral liposome delivery systems remain an active area for innovations in expanding their applications. It is anticipated that demand for oral liposomal drug‑delivery systems will continue to grow, driven by the rising prevalence of chronic diseases that require long‑term therapeutic management.

Glioblastoma (GBM) remains a highly lethal form of cancer due to its molecular heterogeneity and the immunosuppressive microenvironment surrounding the tumor. Here, we report a modular immunotherapy platform characterized by its flexibility to simultaneously target multiple antigens. Specifically, we utilize engineered E. coli Nissle to colonize tumors and produce bispecific engagers that simultaneously target EGFRvIII and interleukin (IL)-13Rα2. These tags direct in situ-reprogrammed chimeric antigen receptor (CAR) macrophages, which are edited using nanoparticles and delivered within a shear-thinning hydrogel, to execute targeted phagocytosis. This probiotic-macrophage crosstalk eliminates tumor cells while converting protumor M2 macrophages into immunostimulatory M1 effectors. In aggressive orthotopic GBM mouse models, this strategy achieves 83% survival at the 120-day endpoint, representing a 5-fold improvement over single-target controls and establishing durable immunological memory that effectively combats recurrence. By functioning as multifunctional immune hubs, this platform offers a versatile framework designed to overcome the antigenic complexity of solid tumors.

There is increasing evidence that nuclear receptor subfamily 1 group I member 3 (NR1I3) plays a significant role in the progression of many malignancies. However, it is unclear whether NR1I3 suppresses colorectal cancer (CRC) growth or alters gluconeogenesis. Western blotting, flow cytometry analysis, cell proliferation, colony formation assays, quantitative real-time polymerase chain reaction (qRT‒PCR), gluconeogenesis tests, and animal models were used to examine the functional role of NR1I3 in CRC cells. We found that NR1I3 was frequently downregulated in CRC tissue and that low NR1I3 expression was strongly correlated with poor patient survival. Subsequent in vitro and in vivo functional tests demonstrated that NR1I3 significantly inhibited proliferation and induced apoptosis in CRC cells by arresting the cell cycle in the G2/M phase. We also found that pharmacologically inducing NR1I3 with 6-(4-chlorophenyl) imidazo[2,1-b][1,3] thiazole-5-carbaldehydeO-(3,4-dichlorobenzyl) oxime (CITCO) reduced CRC cell growth and induced apoptosis in vitro and in vivo. Furthermore, we demonstrated that CITCO can influence gluconeogenesis activity by influencing genes in the gluconeogenesis pathway. Notably, NR1I3 increases gluconeogenesis and inhibits glycolysis by interacting with phosphoenolpyruvate carboxykinase 1 (PCK1), the enzyme that limits the rate of gluconeogenesis. This leads to ATP depletion, and cell growth is halted. These findings suggest that NR1I3 inhibits CRC by converting glycolysis to gluconeogenesis via PCK1, suggesting potential indicators and treatment targets for CRC progression.

Innate immunity is crucial in orchestrating the brain immune response, however, glioblastoma multiforme (GBM) has evolved sophisticated mechanisms to evade innate immune surveillance, posing significant challenges for current immunotherapies. Here, a therapeutic strategy is reported that aims at reactivating innate immune responses in GBM via targeted induction of mitochondrial stress, thereby enhancing tumor immunogenicity. Specifically, innate immune-stimulating nanoparticles (INSTNA) are developed, encapsulating positively charged iridium-based complexes (Ir-mito) and small interfering RNA against Methylation-Controlled J protein (si-MCJ) to attenuate mitochondrial respiration. This combination effectively disrupts mitochondrial function of GBM cells, particularly when combined with tumor-treating fields. The engineered charge-reversal INSTNA impair the mitochondrial electron transport chain (ETC), inducing oxidative phosphorylation (OXPHOS) stress and subsequent mitochondrial matrix release. Furthermore, hydrogel-mediated delivery of INSTNA in a postoperative GBM mouse model significantly remodeled the immunosuppressive microenvironment, resulting in pronounced tumor regression. In sum, these findings highlight that targeted induction of mitochondrial stress in postoperative GBM can potentiate innate immune activation and enhance adaptive immunity, offering a promising avenue for mitigating GBM recurrence.

With prevalence of bacterial resistance and decline in antibiotic development, immunotherapy is emerging as a promising strategy for bacterial infections. Macrophages play a crucial role in bacterial eradication and lipopolysaccharide (LPS) detoxification. However, overactivated macrophages triggered by excess LPS can also induce inflammatory injury and impaired antimicrobial response. Therefore, nanotherapies that synergize with and/or steer macrophages to simultaneously eliminate bacteria and LPS, provide an optimal strategy for immunomodulation to achieve a balance between antimicrobial and inflammatory responses. Inspired by antibody-drug conjugates (ADCs), we report a peptide-nanoparticle conjugate (PNC) composed of opsonized peptides (B-mBPI) and engineered nanoparticle (PEGylated liposomes loaded with antibiotic). This PNC could effectively neutralized LPS with high affinity and specifically tag bacteria, then guiding macrophages towards the elimination of bacteria and LPS. With this steering-elimination function, a synergistic interaction was observed by evaluating the combination index (CI) of PNC and macrophages towards the antibacterial effect (CI = 0.103 < 1). Besides, we found that the dual-route administration regimen combining intraperitoneal (i.p) and intravenous (i.v) delivery of PNC demonstrated superior therapeutic efficacy compared to single-route therapy in intraperitoneal infection, highlighting the importance of tailoring nanocarrier delivery to infection dynamics. Consequently, this PNC significantly reduced the bacterial burden by more than 3 orders of magnitude and effectively reduce inflammatory factors (TNF-alpha, IL-6) and LPS levels to baseline, leading to a substantial improvement in the survival rate of mice infected with drug-resistant Escherichia coli (E. coli) (0 % improved to 71.4 %). This PNC presents a paradigm for antimicrobial immunotherapy by steering elimination of bacteria and LPS as well as modulating immune response.

BACKGROUND:Tumour hypoxia poses a significant challenge in cancer treatment. There is mounting evidence that reoxygenating tumours increases their sensitivity to conventional cancer therapies. Oxygenated microbubbles (OMB) show promise for this application but suffer from poor stability and rapid clearance. Embedding OMB in a thermosensitive hydrogel (OMBHG) may prolong tumour oxygenation and improve therapeutic outcomes. OBJECTIVES:To formulate and evaluate OMB loaded in a temperature sensitive hydrogel on an in vitro model of tumour hypoxia. METHODS:OMB generated from a liposomal precursor were dispersed at various concentrations in a poloxamer hydrogel. OMB size, hydrogel rheology, injectability, oxygen loading/release, and impact on efficacy of radiotherapy against HCT116 colon cancer cells under hypoxia/normoxia were evaluated. RESULTS:DSPC:DSPE-PEG2000 (94:6 molar ratio) liposomes dispersed in a poloxamer 407: poloxamer 188 (21:6.5 % w/w) hydrogel generated OMB predominantly sized < 1 µm. OMBHG formulations were deemed injectable (force to inject < 38 N) at 20 °C and gelled before 37 °C and demonstrated both greater oxygen loading and prolonged oxygen release than OMB alone. Cancer cells were significantly less sensitive to radiotherapy under hypoxic conditions. Pre-treatment of the cells with OMB or OMBHG enhanced radiotherapy significantly, reducing clonogenic survival rates in HCT116 cells by 78 % in hypoxic conditions and by 68 % in normoxic conditions (p < 0.0001 in both cases). Notably, this treatment restored the radiotherapy sensitivity of hypoxic cells to the levels seen with normoxic cells. CONCLUSION:Reoxygenation with a newly developed OMB hydrogel formulation effectively sensitised HCT116 to radiotherapy in vitro. Ongoing studies are exploring the importance of reoxygenation rate and extent for optimal tumour sensitisation.

For many decades, conventional pharmaceutical excipients have been used to optimize the palatability, processing ability, flowability, and compressibility of various types of medication throughout the production process [...]

The Warburg effect, which is aerobic glycolysis, constitutes a major driver of various cancer progression. Therefore, we aimed to examine the role of peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC1α) and its competing endogenous RNA (ceRNA) network in colorectal cancer (CRC) metabolic reprogramming. We used bioinformatics analysis and dual-luciferase reporter gene experiments and identified the DNMBP-AS1/hsa-miR-30a-5p/PGC1α ceRNA network. Additionally, we investigate the impact of PGC1α expression alterations on CRC proliferation and metabolic reprogramming. Moreover, we studied the influence of PGC1α on pyruvate kinase M2 (PKM2), and CRC malignant behavior manifestation. Our study has uncovered a significant association between the DNMBP-AS1/hsa-miR-30a-5p/PGC1α ceRNA network and CRC patient prognosis. Additionally, PGC1α overexpression impeded CRC growth, reduced glycolytic capacity, and enhanced anti-PD-1 therapy efficacy. PGC1α inhibited tumor cell glycolysis by downregulating the WNT/β-catenin pathway depending on peroxisome proliferator-activated receptor gamma (PPARγ), thereby suppressing PKM2. The PPARγ agonist rosiglitazone could hinder CRC proliferation and glycolytic activity. Combined with the PGC1α agonist ZLN005, it exhibits synergistic effects for treating CRC. Moreover, we verified that ZLN005 significantly potentiated PD-1 induced tumor suppression in xenograft mice. Finally, we demonstrated that PGC1α and PKM2 expression patterns in tumor tissues were closely related to patient prognosis. Moreover, we constructed a predictive model to predict the 5-year survival events in CRC patients using random forest model. Our results offer novel perspectives on the role of DNMBP-AS1/hsa-miR-30a-5p/PGC1α network in controlling CRC proliferation, metabolism and immune responses. Furthermore, our investigation reveals that using rosiglitazone combined with PGC1α agonist presents a promising therapeutic approach for managing CRC.

BACKGROUND:V-set and immunoglobulin domain containing 4 (VSIG4) is a B7-family-related protein almost exclusively expressed on macrophages. The difference in its expression mediates the dynamic transformation of the polarization state of macrophages, but the underlying mechanism is still unclear. We sought to reveal the correlation between VSIG4 and the polarization of tumour-associated macrophages (TAMs) and the immune escape of tumour cells in colorectal cancer (CRC). METHODS:THP-1 monocyte-derived macrophages expressing different levels of VSIG4 were used for in vitro investigations. In addition, the co-culture system was used to verify the effect of tumour cells on the expression of VSIG4 in macrophages, and the effect of VSIG4 expression level on tumour cells in turn. Subcutaneous xenograft models evaluated the tumour growth inhibition efficacy of VSIG4 blockade as monotherapy and combined with immune checkpoint inhibitors (ICIs). RESULTS:CRC cells secreted lactate to promote VSIG4 expression in macrophages. On the contrary, VSIG4 promoted macrophage M2 polarization and induced malignant progression of tumour cells by promoting M2 macrophage secretion of heparin-bound epidermal growth factor. In vivo experiments confirmed that knockdown VSIG4 inhibited tumour growth and improved the efficacy of ICIs therapy. Mechanistically, lactate secreted by CRC cells promoted its expression by influencing the epigenetic modification of VSIG4 in macrophages. In addition, VSIG4 enhanced the fatty acid oxidation (FAO) of macrophages and upregulated PPAR-γ expression by activating the JAK2/STAT3 pathway, which ultimately induced M2 polarization of macrophages. Downregulation of VSIG4 or blocking of FAO reversed the M2 polarization process of macrophages. CONCLUSIONS:Our findings provide a molecular basis for VSIG4 to influence TAMs polarization by regulating the reprogramming of FAO, suggesting that targeting VSIG4 in macrophages could enhance the ICIs efficacy and represent a new combination therapy strategy for immunotherapy of CRC. KEY POINTS:Colorectal cancer cells secrete lactate to upregulate VSIG4 in macrophages via the H3K18la-METTL14-m6A axis. VSIG4 promotes fatty acid oxidation of macrophages and drives its M2-type polarization. These VSIG4-expressing M2 macrophages promote tumour progression and an immunosuppressive microenvironment. Inhibition of VSIG4 expression can synergistically enhance the therapeutic effect of anti-PD-1 antibody.