º£½ÇÆƽâ°æ

IntroductionTumor-associated macrophages (TAMs) promote immunosuppression, hindering immune checkpoint blockade and immunotherapy efficacy. To overcome this, we developed a novel multifunctional nanovaccine based on hepatitis B core virus-like particles (HBc VLP) to synergistically remodel the immunosuppressive tumor microenvironment through integrated TAM reprogramming and B7-H3 checkpoint blockade.MethodsThe core VLP co-displayed tumor antigen peptide MAGE-A10 and TAM-targeting peptide M2pep via fusion expression. Immunostimulatory CpG oligodeoxynucleotide 1826 (CpG) was encapsulated within VLP. Anti-B7-H3 antibody (¦ÁB7-H3) and polyethylene glycol (PEG) were chemically conjugated to the surface for checkpoint blockade and prolonged circulation, forming CpG@VLP-¦ÁB7-H3-PEG.ResultsStructural characterization using transmission electron microscopy and dynamic light scattering confirmed the hollow spherical self-assembly of VLP. Nanovaccines efficiently targeted TAMs in vitro and in vivo. Following CpG encapsulation (5.60 ?g/mg), the nanovaccine reprogrammed M2-like TAMs into an M1-like phenotype. This was achieved by elevating the M1/M2 ratios of CD86/CD206 and MHC II/CD206 to 15.50-fold and 3.11-fold, respectively, as determined by flow cytometry. Further conjugation of ¦ÁB7-H3 (250 ?g/mg) significantly enhanced T-cell activation in TAM-T cell co-culture assays. In B16-F10 melanoma-bearing mice, reprogrammed iNOS+ M1-like macrophages triggered robust antitumor immunity, achieving a tumor inhibition rate of 63.47%. These macrophages also function as antigen-presenting cells and increase the proportion of tumor-infiltrating Granzyme B+CD8+ T cells. ¦ÁB7-H3 conjugation further boosted infiltrating immune cells, M1-like macrophages, activated CD69+CD4+/CD8+ T cells, and cytotoxic T lymphocytes. PEGylation amplified systemic tumor-specific immunity and increased tumor inhibition by 80.12%.ConclusionThis HBc VLP-based nanovaccine constitutes a pioneering multifunctional platform designed to overcome TAM-mediated immunosuppression through synergistic integration of three modalities: antigen presentation, TAM phenotype reprogramming, and B7-H3 checkpoint blockade. To the best of our knowledge, this is the first nanovaccine architecture to enable coordinated immunomodulation. Its modular design supports the clinical translation of solid tumors and personalized immunotherapy. Graphical Abstract

Metabolite nutrients within the tumor microenvironment shape both tumor progression and immune cell functionality. It remains elusive how the metabolic interaction between T cells and tumor cells results in different anti-cancer immunotherapeutic responses. Here, we use untargeted metabolomics to investigate the metabolic heterogeneity in patients with colorectal cancer (CRC). Our analysis reveals enhanced S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) metabolism in microsatellite stable (MSS) CRC, a subtype known for its resistance to immunotherapy. Functional studies reveal that SAM and SAH enhance the initial activation and effector functions of CD8+ T cells. Instead, cancer cells outcompete CD8+ T cells for SAM and SAH availability to impair T cell survival. In vivo, SAM supplementation promotes T cell proliferation and reduces exhaustion of the tumor-infiltrating CD8+ T cells, thus suppressing tumor growth in tumor-bearing mice. This study uncovers the metabolic crosstalk between T cells and tumor cells, which drives the development of tumors resistant to immunotherapy.Supplementary InformationThe online version contains supplementary material available at 10.1186/s40170-025-00394-2.

BackgroundDendritic cell (DC)-mediated antigen presentation is essential for the priming and activation of tumor-specific T cells. However, few drugs that specifically manipulate DC functions are available. The identification of drugs targeting DC holds great promise for cancer immunotherapy.MethodsWe observed that type 1 conventional DCs (cDC1s) initiated a distinct transcriptional program during antigen presentation. We used a network-based approach to screen for cDC1-targeting therapeutics. The antitumor potency and underlying mechanisms of the candidate drug were investigated in vitro and in vivo.ResultsSitagliptin, an oral gliptin widely used for type 2 diabetes, was identified as a drug that targets DCs. In mouse models, sitagliptin inhibited tumor growth by enhancing cDC1-mediated antigen presentation, leading to better T-cell activation. Mechanistically, inhibition of dipeptidyl peptidase 4 (DPP4) by sitagliptin prevented the truncation and degradation of chemokines/cytokines that are important for DC activation. Sitagliptin enhanced cancer immunotherapy by facilitating the priming of antigen-specific T cells by DCs. In humans, the use of sitagliptin correlated with a lower risk of tumor recurrence in patients with colorectal cancer undergoing curative surgery.ConclusionsOur findings indicate that sitagliptin-mediated DPP4 inhibition promotes antitumor immune response by augmenting cDC1 functions. These data suggest that sitagliptin can be repurposed as an antitumor drug targeting DC, which provides a potential strategy for cancer immunotherapy.