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T cell infiltration and proliferation in tumor tissues are the main factors that significantly affect the therapeutic outcomes of cancer immunotherapy. Emerging evidence has shown that interferon-gamma (IFN γ) could enhance CXCL9 secretion from macrophages to recruit T cells, but Siglec15 expressed on TAMs can attenuate T cell proliferation. Therefore, targeted regulation of macrophage function could be a promising strategy to enhance cancer immunotherapy via concurrently promoting the infiltration and proliferation of T cells in tumor tissues. We herein developed reduction-responsive nanoparticles (NPs) made with poly (disulfide amide) (PDSA) and lipid-poly (ethylene glycol) (lipid-PEG) for systemic delivery of Siglec15 siRNA (siSiglec15) and IFN γ for enhanced cancer immunotherapy. After intravenous administration, these cargo-loaded could highly accumulate in the tumor tissues and be efficiently internalized by tumor-associated macrophages (TAMs). With the highly concentrated glutathione (GSH) in the cytoplasm to destroy the nanostructure, the loaded IFN γ and siSiglec15 could be rapidly released, which could respectively repolarize macrophage phenotype to enhance CXCL9 secretion for T cell infiltration and silence Siglec15 expression to promote T cell proliferation, leading to significant inhibition of hepatocellular carcinoma (HCC) growth when combining with the immune checkpoint inhibitor. The strategy developed herein could be used as an effective tool to enhance cancer immunotherapy. Interferon-gamma (IFNγ) recruits T cells, while Siglec15 on tumor-associated macrophages hampers the proliferation. Reduction-responsive nanoparticles delivering siSiglec15 and IFNγ combined with immune checkpoint inhibitors could inhibit hepatocellular carcinoma growth. [Display omitted] [ABSTRACT FROM AUTHOR]

Increasing evidence suggests that the presence and spatial localization and distribution pattern of tumor infiltrating lymphocytes (TILs) is associate with response to immunotherapies. Recent studies have identified TGF β activity and signaling as a determinant of T cell exclusion in the tumor microenvironment and poor response to PD-1/PD-L1 blockade. Here we coupled the artificial intelligence (AI)-powered digital image analysis and gene expression profiling as an integrative approach to quantify distribution of TILs and characterize the associated TGF β pathway activity. Analysis of T cell spatial distribution in the solid tumor biopsies revealed substantial differences in the distribution patterns. The digital image analysis approach achieves 74% concordance with the pathologist assessment for tumor-immune phenotypes. The transcriptomic profiling suggests that the TIL score was negatively correlated with TGF β pathway activation, together with elevated TGF β signaling activity observed in excluded and desert tumor phenotypes. The present results demonstrate that the automated digital pathology algorithm for quantitative analysis of CD8 immunohistochemistry image can successfully assign the tumor into one of three infiltration phenotypes: immune desert, immune excluded or immune inflamed. The association between "cold" tumor-immune phenotypes and TGF β signature further demonstrates their potential as predictive biomarkers to identify appropriate patients that may benefit from TGF β blockade. An artificial intelligence-powered digital image analysis approach has been established to characterize and classify the cancer immune phenotypes, which might be utilized as predictive biomarkers for TGF β blockade therapy. [Display omitted] [ABSTRACT FROM AUTHOR]

Glucose metabolism is known to orchestrate oncogenesis. Whether glucose serves as a signaling molecule directly regulating oncoprotein activity for tumorigenesis remains elusive. Here, we report that glucose is a cofactor binding to methyltransferase NSUN2 at amino acid 1–28 to promote NSUN2 oligomerization and activation. NSUN2 activation maintains global m5C RNA methylation, including TREX2 , and stabilizes TREX2 to restrict cytosolic dsDNA accumulation and cGAS/STING activation for promoting tumorigenesis and anti-PD-L1 immunotherapy resistance. An NSUN2 mutant defective in glucose binding or disrupting glucose/NSUN2 interaction abolishes NSUN2 activity and TREX2 induction leading to cGAS/STING activation for oncogenic suppression. Strikingly, genetic deletion of the glucose/NSUN2/TREX2 axis suppresses tumorigenesis and overcomes anti-PD-L1 immunotherapy resistance in those cold tumors through cGAS/STING activation to facilitate apoptosis and CD8+ T cell infiltration. Our study identifies NSUN2 as a direct glucose sensor whose activation by glucose drives tumorigenesis and immunotherapy resistance by maintaining TREX2 expression for cGAS/STING inactivation. [Display omitted] • Glucose promotes oligomerization and activation of NSUN2 by its direct binding to NSUN2 • The glucose/NSUN2 axis maintains TREX2 expression to execute its oncogenic activity • The axis represses cGAS/STING activation to maintain oncogenic activity of cancer cells • The axis drives anti-PD-L1 immunotherapy resistance by restricting cGAS/STING signaling Whether glucose is a signaling molecule directly regulating oncoproteins for tumorigenesis remains elusive. Chen et al. identify NSUN2 as a direct glucose sensor driving tumorigenesis and immunotherapy resistance by maintaining TREX2 expression for cGAS/STING inactivation, thus opening a new avenue for studying novel glucose's actions in regulating diverse biological processes. [ABSTRACT FROM AUTHOR]

The insufficient infiltration of T cells in solid tumors hinders the therapeutic efficacy of immune checkpoint blockade (ICB) antibodies and chimeric antigen receptor (CAR)-T cells. Promoting T or CAR-T cells to efficiently and specifically migrate into solid tumors is critical for improving current immunotherapies, which remains a challenge. Herein, we proposed a CRISPR-based transcriptional activation (CRISPRa) nanomedicine for mobilizing tumor cells to recruit T cells by activating the expression of T cell chemokines CXC-chemokine ligand (CXCL) 9, CXCL10, and CXCL11. We demonstrated that the CRISPRa nanomedicine could dramatically upregulate the expression of these T cell chemokines in tumor cells, thereby facilitating T cell migration directionally into solid tumors. Intratumoral injection of the CRISPRa nanomedicine inhibited the growth of different solid tumors including melanoma, pancreatic, colonic, and breast cancers. Moreover, tumor-specific versions of the CRISPRa nanomedicine possessing the ability to upregulate the T cell chemokine expression only in tumors rather than normal tissues or cells were constructed. Systemic injection of the tumor-specific CRISPRa nanomedicine specifically recruited T or CAR-T cells into solid tumors and improved the therapeutic effects of ICB antibodies (anti-PD-L1 or anti-CTLA4) and CAR-T cells. Thus, the gene-activating nanomedicine provides a promising strategy for enhancing T cell infiltration to improve current immunotherapies against solid tumors. [Display omitted] • CRISPRa nanomedicine recruited effector T cells into tumors via activating T cell chemokines. • Tumor-specific CRISPRa nanomedicine could activate only tumors rather than normal organs to express T cell chemokines. • Systemic injection of the tumor-specific CRISPRa nanomedicine enhanced the efficacy of ICB antibodies and CAR-T cells. [ABSTRACT FROM AUTHOR]