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PubMed2026

A murine model of sepsis induces age- and sex-specific chromatin remodeling in myeloid-derived suppressor cells.

INTRODUCTION: Sepsis survivors frequently develop long-term immune dysfunction, but the epigenetic mechanisms underlying persistent myeloid suppression remain unclear. Myeloid-derived suppressor cells (MDSCs), whose function is shaped by host age and sex, are key contributors to post-sepsis immune dysregulation. METHODS: Here, we present a high-resolution epigenetic map targeting gene promoters of MDSCs after sepsis and daily chronic stress using MAPit-FENGC, a single-molecule assay that simultaneously profiles DNA methylation and chromatin accessibility. In a clinically relevant murine model, including young and older adult male and female mice, splenic MDSCs were isolated for MAPit-FENGC and single-cell RNA sequencing. RESULTS: Unsupervised clustering identified nine promoter classes reflecting chromatin dynamics: age- and sex-dependent sepsis-induced opening (Classes 1-4), persistent closure with varying levels of DNA methylation (Classes 5-7), and constitutive openness post-sepsis (Classes 8, 9). Transcriptomic profiling corroborated these promoter states, linking accessibility with gene expression. CONCLUSIONS: These findings define promoter-level epigenetic classes across a targeted locus panel in splenic CD11b+Gr1+ cells within this murine sepsis model and generate mechanistic hypotheses regarding age- and sex-associated chromatin states.

Animals↗

PubMed2025

Immune microenvironment in hepatocellular carcinoma: from pathogenesis to immunotherapy.

Hepatocellular carcinoma (HCC) is an increasingly prevalent and deadly disease that is initiated by different etiological factors, such as alcohol-associated liver disease (ALD), metabolic dysfunction-associated steatohepatitis (MASH), viral hepatitis, and other hepatotoxic and hepatocarcinogenic agents. The tumor microenvironment (TME) of HCC is characterized by several different fibroblastic and immune cell types, all of which affect the initiation, progression and metastasis of this malignant cancer. This complex immune TME can be divided into an innate component that includes macrophages, neutrophils, dendritic cells, myeloid-derived suppressor cells, mucosal-associated invariant T cells, natural killer cells, natural killer T cells, and innate lymphoid cells, as well as an adaptive component that includes CD4+ T cells, CD8+ T cells, regulatory T cells, and B cells. In this review, we discuss the latest findings shedding light on the direct or indirect roles of these immune cells (and fibroblastic-like cells such as hepatic stellate cells) in the pathogenesis of HCC. Henceforth, further characterization of this heterogeneous TME is highly important for studying the progression of HCC and developing novel immunotherapeutic treatment options. In line with this, we also review novel groundbreaking experimental techniques and animal models aimed at specifically elucidating this complex TME and discuss emerging immune-based therapeutic strategies intended to treat HCC and predict the efficacy of these immunotherapies.

Humans↗

PubMed2025

Identification and external validation of a prognostic signature based on myeloid-derived suppressor cells-related LncRNAs to evaluate survival prognosis and treatment efficacy in invasive breast carcinoma.

BACKGROUND: Originating in the hematopoietic tissue, myeloid-derived suppressor cells (MDSCs) significantly contribute to tumor-related immunological processes. However, their relationship with long noncoding RNAs (lncRNAs) and breast cancer remains incompletely understood. In this study, we introduced MDSCs-associated lncRNAs as novel prognostic biomarkers to assess outcomes in patients with invasive breast carcinoma (BRCA). METHODS: Information regarding BRCA cases, including clinical and genomic details, was obtained from the TCGA repository. Predictive indicators were discovered, and their reliability underwent thorough verification. A clinically useful nomogram was developed following application-based validation. Additional investigations encompassed functional analysis, TMB assessment, TME profiling, immunotherapy efficacy forecasting, and drug sensitivity testing along with target identification. Long non-coding RNA expression was measured using reverse transcription quantitative PCR. RESULTS: A risk stratification model incorporating eight MDSCs-related lncRNAs effectively predicted patient outcomes. Kaplan-Meier (K-M) survival analysis clearly indicated a much worse prognosis among patients classified as high-risk (p < 0.001). The nomogram accurately forecasted overall survival (OS). Analysis of functional enrichment revealed that pathways associated with epithelial cells showed activity among patients at higher risk. Characterization of the tumor microenvironment showed increased immune cell presence in those classified as low-risk. Conversely, individuals with greater risk displayed higher tumor mutational burden. TIDE and IPS analyses indicated superior immunotherapy responsiveness in the low-risk BRCA subgroup. Among 47 drugs with notable IC50 variations, Ribociclib, PD173074, KU-55933, NU7441, and nutlin-3a exhibited lower IC50 values within the low-risk group, whereas Lapatinib demonstrated greater efficacy among the high-risk group. Moreover, 10 potential therapeutic agents and their targets were predicted for high-risk patients. RT-qPCR validation confirmed the robustness of the model. CONCLUSIONS: We successfully verified a new model of molecular markers of MDSCs-related lncRNAs, offering critical insights for predicting outcomes and guiding therapeutic decisions in BRCA cases.

Bioinformatics↗

PubMed2025

Deep immune profiling of intrahepatic cholangiocarcinoma with CODEX multiplexed imaging.

BACKGROUND: Intrahepatic cholangiocarcinoma (iCCA) may be genomically subclassified by the presence of potentially actionable molecular aberrations, of which pathogenic alterations in isocitrate dehydrogenase (IDH)1 and fibroblast growth factor receptor (FGFR)2 are the most frequently observed. The impact of these molecular alterations on the tumor immune microenvironment remains incompletely understood. METHODS: We performed a high-parameter spatial immune phenotyping of iCCA samples with pathogenic FGFR2 or IDH1 alterations and FGFR2/IDH1 wild-type controls at the single-cell level using CO-Detection by indEXing. RESULTS: A total of 24 tumors were examined. Tumors with FGFR2 alterations were characterized by fewer CD8+ T cells and "M2-like" macrophages but higher levels of polymorphonuclear myeloid-derived suppressor cells as compared to FGFR2 wild-type tumors. Spatial relationships between polymorphonuclear myeloid-derived suppressor cells and multiple other cell types in the tumor microenvironment (including tumor cells, CD4+, and CD8+ T cells) were enriched in tumors with FGFR2 alterations. Tumors with IDH1 mutations had a trend toward more fibroblasts and were characterized by a closer proximity of tumor cells to CD4+ T cells, and between macrophages and multiple structural tumor microenvironment components as compared to other subtypes. CONCLUSIONS: iCCAs with pathogenic FGFR2 fusions/rearrangements and IDH1 mutations have distinct immunophenotypes. Tailoring immunotherapeutic approaches to specific molecular subsets could improve treatment outcomes across the divergent molecularly defined iCCA subtypes.

Humans↗

PubMed2025

Rewiring tumor immunity via zinc finger proteins: a new frontier in cancer immunotherapy.

BACKGROUND: Zinc finger proteins (ZFPs) represent the largest and most structurally diverse family of transcription factors in the human genome. They function through characteristic zinc finger domains that enable specific binding to DNA, RNA, and proteins, playing a central regulatory role in the tumor immune microenvironment. MAIN BODY: This review systematically examines the dual functions of ZFPs in dynamically regulating both innate and adaptive immune responses in cancer. At the innate immunity level, ZFPs precisely control dendritic cell (DC) fate determination, dictate macrophage polarization, balance natural killer (NK) cell activation, mediate myeloid-derived suppressor cell (MDSC) immunosuppressive function, and modulate innate immune sensors and inflammasomes. Within adaptive immunity, ZFPs critically influence T cell effector function and regulate B cell differentiation. Building on these, diverse immunotherapeutic strategies targeting ZFPs are now emerging. These include gene-editing, small molecules and proteolysis-targeting chimeras (PROTACs), synergistic combinations with immune checkpoint blockade, and ZFP-engineered chimeric antigen receptor T (CAR-T) cells. CONCLUSIONS: As pivotal nodes within the tumor immune regulatory network, ZFP-targeting strategies offer novel opportunities to overcome current therapeutic bottlenecks.

Humans↗

PubMed2026

MIF-CD74 axis facilitates MDSC infiltration in the tumor microenvironment of pancreatic ductal adenocarcinoma.

Immune checkpoint inhibitors show insufficient efficacy against pancreatic ductal adenocarcinoma (PDAC). The tumor microenvironment (TME) has a remarkable influence on responsiveness to cancer immunotherapy. The aim of this study was to investigate immunosuppressive characteristics of TME in PDAC tissues. The flow cytometry (FCM) of PDAC surgical specimens revealed that the profile of tumor-infiltrating leukocytes was classified into myeloid cell- and T-cell-dominant subtypes; the myeloid subtype was associated with poorer patient outcomes. Myeloid-derived suppressor cells (MDSCs) showed the highest hazard ratio among various myeloid cell types. Single-cell RNA sequencing and FCM revealed that most MDSCs, but not lymphocytes, in PDAC tissues characteristically express CD74. Macrophage migration inhibitory factor (MIF), a CD74 ligand, was highly expressed in cancer-associated fibroblasts (CAFs) and cancer cells. Spatial transcriptomics demonstrated that the MIF-CD74+ myeloid cell interaction was recognized in CAF-dominant areas in PDAC tissue. CAFs expressing immune suppressor molecules such as MFAP5 and LRRC15 were consistent with MIF+ CAFs. Furthermore, MIF+ CAFs enhanced the migratory activity of MDSCs and promoted MDSC induction and activation. In the murine model, MDSCs were significantly increased in MIF-expressing PDAC tumors, as were CD74+ M-MDSCs per M-MDSC, confirming in vivo interaction between CD74 and MIF. MDSCs play a crucial role in creating an immunosuppressive TME in PDAC; the MIF-CD74 axis drives interactions between MDSCs and CAFs.

Humans↗

PubMed2026

Oxidative stress and cancer: current insights and therapeutic implications.

OXIDATIVE STRESS: good or evil? Oxidative stress occurs when the balance between reactive oxygen species (ROS) and antioxidant defenses shifts toward an excess of ROS; while essential in physiological processes, it plays a context-dependent role in cancer, contributing to both the promotion and inhibition of tumorigenesis. Small to moderate amounts of ROS activate pathways supporting tumor progression and proliferation, while large amounts lead to genomic instability and cell death. ROS are generated endogenously and exogenously. In cancer, ROS activate pathways that prompt tumor development (KRAS, MYC, PI3K-Akt-mTOR) and block tumor suppressors (p53, BRCA1), allowing tumorigenesis and drug resistance. They also modulate the tumor microenvironment (TME) by altering tumor, stromal and immune cell interactions, which initiate angiogenesis, epithelial-mesenchymal transition (EMT), inflammation and metastasis. Myeloid-derived suppressor cells (MDSCs) and cancer-associated fibroblasts (CAFs) contribute to ROS-driven immunosuppression. Cancer cells mainly rely on glycolysis and oxidative phosphorylation (OXPHOS) to sustain their energetic and metabolic requirements. Generated ROS act as metabolic byproducts and signaling molecules supporting proliferation and tumorigenesis. Cancer stem cells (CSCs) produce low ROS levels by activating antioxidant pathways and mitochondria remodeling, ensuring recurrence and persistence. There is a redox duality that presents challenges and opportunities for therapies. Pro-oxidant approaches attempt to overwhelm the tumor's defenses, while antioxidants preserve healthy tissues. Advances in targeted redox modulation with immunotherapies improve therapy effectiveness. We propose a new "Adaptive Directed Redox Therapy" (ADRT), which involves a dynamic, feedback-controlled methodology that alternates pro- and antioxidant phases to selectively collapse tumor redox balance while preserving normal tissues.

Humans↗

PubMed2025

Immune landscape and novel therapeutic targets of epidermal growth factor receptor and anaplastic lymphoma kinase wild type never-smoker lung adenocarcinoma.

BACKGROUND: Never-smoker lung adenocarcinoma (NSLA) exhibits distinct immunosuppressive profiles and a lower tumor mutation burden compared with lung adenocarcinoma in smokers. These correlate with poor responses to immune checkpoint inhibitors. In this study, we aimed to elucidate the tumor-immune microenvironment of NSLA without epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) alterations and identify novel therapeutic targets. METHODS: We analyzed genome, transcriptome, and proteomic data from 102 NSLA tumor samples and 16 normal adjacent tissues. We classified tumors into distinct immune clusters (IC) based on gene signatures by profiling the tumor-infiltrating immune cells. RESULTS: The tumors were stratified into three ICs: hot, intermediate, and cold. Notably, only 21 (20.6%) patients exhibited hot IC enriched in cytotoxic T cells, natural killer cells, and B-cell signatures, which correlated with improved recurrence-free survival. Cold ICs (37.3%) exhibited higher myeloid-derived suppressor cell (MDSC) levels and M2 macrophage signatures, with poor immune cell infiltration and relatively low stimulatory cytokines and chemokines expression. CEACAM1, and NECTIN2 were upregulated in intermediate and cold ICs and correlated with MDSC and M2 macrophage infiltration. High expression of these genes was associated with poor survival outcomes. Protein-protein network analysis of 20 upregulated molecules associated with cancer- and driver-related proteins in cold IC identified XPO 1 as a key component. CONCLUSION: Our proteogenomic analysis highlighted the immunosuppressive properties of NSLA without EGFR and ALK alterations and identified novel therapeutic targets. These findings may provide novel treatment strategies that could improve the clinical outcomes of patients with NSLA.

Humans↗

PubMed2025

Population analysis and immunologic landscape of melanoma in people living with HIV.

PURPOSE: To dissect the clinical and immunological features of people living with HIV (PLWH) diagnosed with melanoma, who have consistently exhibited worse clinical outcomes than HIV-negative individuals (PLw/oH) with the same cancer. EXPERIMENTAL DESIGN: We analyzed electronic health records from 1,019 PLWH and 373,121 PLw/oH diagnosed with melanoma. Demographic and clinical characteristics were compared. Spatial immune transcriptomics (72 immune-related genes) was performed on melanoma tumor samples (n=11), followed by downstream validation using multiplex immunofluorescence (n=15 PLWH, n=14 PLw/oH). RESULTS: PLWH were diagnosed with melanoma at a younger age, had a higher representation of Hispanic and Black individuals compared to PLw/oH, and a decreased survival rate. PLWH also showed a markedly increased risk of brain metastases. PLWH experienced significant delays in initiating immune checkpoint inhibitor (ICI) therapy and had worse survival outcomes following ICI, even after balancing for demographic covariates. Spatial transcriptomics revealed a more immunosuppressive tumor microenvironment in PLWH, with upregulation of immune checkpoints (PD1, LAG3) and reduced expression of antigen presentation markers (HLA-DRB, B2M), with distinct spatial distributions in tumors and their microenvironments. Multiplex immunofluorescence confirmed an exhausted CD8+ T cell compartment in PLWH, including enrichment of PD1intLAG3- and PD1intLAG3+ subpopulations, and a significant accumulation of immunosuppressive myeloid-derived suppressor cells (CD11b+ HLA-DR- CD33+). CONCLUSIONS: Our findings suggest chronic HIV infection fosters a permissive tumor microenvironment that might undermine effective immune responses and contribute to poor clinical outcomes for PLWH with melanoma. Targeting the actionable immune pathways identified in this study could inform tailored therapeutic strategies to mitigate these disparities.

HIV↗

PubMed2025

Effect of extracellular vesicles in remodeling the tumor microenvironment by DNMT1 downregulation for enhanced cancer immunotherapy.

BACKGROUND: The efficacy of immunotherapy is often hindered by the suppression of immune responses via the tumor microenvironment (TME). The presence of cancer cells forces other proximal non-cancerous cells to support tumor growth and persistence. A clear example of this cancerous-to-non-cancerous communication is represented by the accumulation of myeloid-derived suppressor cells (MDSCs) within the TME. Several studies have convergently shown that the overexpression of DNA-methyl-transferase-1 (DNMT1) in these cells results in protection from necroptosis and enhanced accumulation in vivo. Conversely, targeting DNMT1 through hypo-methylating agents has shown promising therapeutic potential by not only reducing the levels of MDSCs but also enhancing cancer immunogenicity and the efficacy of immune checkpoint inhibitors (ICI). METHODS: Murine 4T1 (triple-negative breast cancer (TNBC)) and CT26 (colon carcinoma) cell lines were cultured under standard conditions and used to generate tumor models in BALB/c mice. An oncolytic adenovirus expressing a DNMT1-targeting short hairpin RNA (OAd.shDNMT1) was engineered and validated for DNMT1 knockdown and genome-wide methylation reduction. Small extracellular vesicles (sEVs) were isolated from virus-infected cancer cells and characterized for RNA content and uptake by MDSCs. MDSC differentiation and suppressive function were assessed in vitro using flow cytometry and co-culture assays with murine splenocytes. In vivo, tumor-bearing mice received intratumoral OAd.shDNMT1, systemic decitabine, or immune checkpoint inhibitors (anti-Programmed cell Death protein-1), and tumor growth, immune infiltration, and systemic MDSC levels were evaluated. RESULTS: In this study, we report that, by using virally infected TNBC murine cells as a source for shDNMT1-loaded sEVs, OAd.shDNMT1 successfully reduced MDSC levels in vitro and in vivo. Furthermore, the co-administration with ICI resulted in a significant tumor growth reduction in mice bearing poorly immunogenic TNBC 4T1 cells. Also, our treatment promoted antitumor immunity, prolonged survival, and complete tumor eradication in modestly immunogenic colon CT26 cancer cells. CONCLUSION: This multifaceted strategy, based on OV-mediated immune stimulation and reduction of MDSC levels via sEVs, may improve clinical outcomes and the success of immuno-based regimens for patients facing MDSC-rich and highly aggressive cancer subtypes.

Animals↗

PubMed2026

Metabolic-cell-death gene trio predicts survival and cuproptosis sensitivity in colorectal cancer.

BACKGROUND: Metabolic cell death (MCD) modulates colorectal cancer (CRC) progression, yet its prognostic value remains unexplored. We aimed to build an MCD-centred gene signature for outcome prediction and precision therapy. METHODS: Transcriptomes of 1,174 CRC patients were integrated. Weighted gene co-expression network analysis, differential expressions and least absolute shrinkage and selection operator (LASSO) + random survival forest were successively applied to derive a three-gene (CDKN2A/MPC1/AHCY) risk model. Functional, immune-infiltration, drug-sensitivity and genomic analyses were performed, followed by validation in fresh clinical specimens and cell lines. RESULTS: Integrative metabolic-death transcriptomics identified CDKN2A, MPC1 and AHCY as the hub drivers of CRC. Their three-gene signature robustly stratified patients into high- and low-risk subsets [3-year area under the curve (AUC) 0.83-0.85, P<0.001]. High-risk tumors were enriched for extracellular matrix (ECM)-receptor-interaction pathways, displayed abundant myeloid-derived suppressor cell (MDSC) infiltration and were more vulnerable to AZD8186, AZ960 and JAK inhibitors. Guided by these in-silico findings, we functionally confirmed that CDKN2A silencing markedly repressed proliferation, invasion and migration of SW480/HCT116 cells and potentiated cuproptosis via up-regulation of lipoylated DLAT/DLST and CTR1. CONCLUSIONS: We report the first MCD-derived prognostic platform for CRC that simultaneously predicts survival and therapeutic response. Targeting CDKN2A-enhanced cuproptosis represents a promising metabolic-precision strategy for high-risk patients.

Colorectal cancer (CRC)↗

PubMed2026

A CFH- and SPINT2-based prognostic signature for cholangiocarcinoma.

BACKGROUND: Cholangiocarcinoma (CCA) is a highly malignant tumor with a poor prognosis, and reliable biomarkers for postoperative risk stratification remain limited. This study aimed to develop and validate a CFH- and SPINT2-based prognostic signature to support postoperative risk stratification and inform adjuvant therapy selection in CCA through integrative machine learning and single-cell transcriptomics. METHODS: Differentially expressed genes were screened from GSE26566. Integrative machine learning (least absolute shrinkage and selection operator-Cox, random forest, and univariate Cox regression) was performed in the training cohort (GSE89749; n=115) to construct a risk model, which was externally validated in two independent cohorts: cohort 1 (E-MTAB-6389; n=75) and cohort 2 [The Cancer Genome Atlas Cholangiocarcinoma (TCGA-CHOL) data set; n=36]. Systematic analysis was conducted and included examinations of immune infiltration [via single-sample gene set enrichment analysis (ssGSEA)], pathway enrichment (via hallmark GSEA), cellular localization (via single-cell RNA sequencing), and drug sensitivity (via the Genomics of Drug Sensitivity in Cancer 2 database). RESULTS: Two genes, CFH and SPINT2, were identified and incorporated into a prognostic risk score. High-risk patients in the training cohort had a significantly worse overall survival (log-rank P=0.02). External validation was performed in two independent cohorts. In validation cohort 1, the risk group was an independent prognostic factor [hazard ratio =2.27, 95% confidence interval (CI): 1.18-4.37; P=0.01]. In validation cohort 2, the model demonstrated acceptable discriminative ability (concordance index =0.721; 3-year area under the curve =0.692). The high-risk group exhibited an immunosuppressive microenvironment characterized by increased infiltration of macrophages and myeloid-derived suppressor cells, along with the activation of epithelial-mesenchymal transition, inflammatory response, and NF-κB signaling pathways. Single-cell analysis revealed a cell-type-specific expression pattern: CFH was predominantly expressed in fibroblasts, while SPINT2 was mainly expressed in malignant cells. Drug sensitivity analysis demonstrated that the high-risk group was more sensitive to gemcitabine, cisplatin, poly(ADP-ribose) polymerase (PARP) inhibitors, and mammalian target of rapamycin (mTOR) inhibitors, whereas the low-risk group was more sensitive to lapatinib. CONCLUSIONS: The CFH- and SPINT2-based prognostic signature may serve as an independent biomarker for postoperative risk stratification in CCA. High-risk patients, characterized by fibroblast-derived CFH enrichment and malignant-cell SPINT2 loss, exhibit an immunosuppressive microenvironment and may be more suitable for gemcitabine-based chemotherapy or PARP/mTOR inhibitors, whereas low-risk patients may benefit from less intensive adjuvant strategies or HER2/EGFR-targeted lapatinib. Prospective validation is warranted before clinical implementation.

Cholangiocarcinoma (CCA)↗

PubMed2025

Oncogenic EME1 promotes tumor progression and immune modulation in human cancers with therapeutic targeting potential.

BACKGROUND: EME1, a critical DNA repair endonuclease, has emerged as a potential oncogene implicated in genome instability and cancer progression. However, its pan-cancer roles, prognostic significance, immune interactions, and therapeutic targeting remain underexplored. METHODS: We conducted a comprehensive pan-cancer analysis integrating multi-omics data from public databases, including TIMER2.0, GEPIA2, TISIDB, and cBioPortal, to evaluate EME1 expression, genetic alterations, and their association with clinical outcomes, immune infiltration, and molecular pathways. Virtual screening of 3180 FDA-approved drugs and molecular dynamics (MD) simulations were employed to identify and validate potential EME1 inhibitors. RESULTS: EME1 was significantly overexpressed in various human cancers and positively associated with advanced tumor grade and stage. High EME1 expression and mutations were linked to poor overall and disease-free survival. Immunogenomic profiling revealed strong positive correlations between EME1 and myeloid-derived suppressor cells (MDSCs), alongside a negative association with endothelial cell function, suggesting immunosuppressive roles. Machine learning models based on EME1-associated genes demonstrated high predictive accuracy for liver hepatocellular carcinoma (AUC > 0.90). Virtual screening identified eight promising drug candidates, including Everolimus and Dioscin, with strong binding affinities. MD simulations confirmed the stability of these interactions, particularly for Dioscin. CONCLUSION: This study reveals the multifaceted oncogenic roles of EME1 in tumor progression, immune evasion, and prognosis. It proposes EME1 as a promising biomarker and therapeutic target across multiple cancer types. The identified drug candidates warrant further in vitro and in vivo validation for potential repurposing in EME1-targeted cancer therapy.

EME1↗

PubMed2026

The gut microbiota-obesity axis in the pathogenesis and prognosis of breast cancer.

BACKGROUND: Breast cancer (BC) remains a major global health concern, accounting for 11.7% of all cancer cases and ranking as the second leading cause of female cancer-related deaths worldwide. Increasing evidence highlights the interplay between gut microbiota (GM) dysbiosis and obesity-associated metabolic dysfunction in BC progression. This review aims to elucidate the role of GM in obese patients with BC. METHODS: A systematic literature search was conducted in PubMed and Web of Science databases for publications from July 2015 to January 2025. Search terms combined BC, GM, obesity, dysbiosis, immunity, and microbiome. Article selection prioritized studies investigating microbial alterations in BC patients, mechanistic links between obesity and cancer progression, and GM-targeted interventions. Both original studies and authoritative reviews were included, supplemented by manual reference screening. DISCUSSION: Obesity may trigger systemic inflammation, altered adipokine secretion, and disrupted steroid hormone metabolism via gut-derived β-glucuronidase activity, thereby exacerbating BC occurrence and recurrence. GM dysbiosis-driven metabolites such as branched-chain amino acids (BCAAs) and short-chain fatty acids (SCFAs) can activate oncogenic signaling pathways and immunosuppressive myeloid-derived suppressor cells (MDSCs), fostering tumor immune evasion. Conversely, dietary interventions, probiotics, and fecal microbiota transplantation (FMT) can alleviate dysbiosis, strengthen gut barriers, and restore anti-tumor immunity, improving chemotherapy response and reducing recurrence. However, challenges persist in deciphering BC subtype-related microbial signatures and optimizing microbiota-targeted therapies. CONCLUSION: Future longitudinal studies are needed to clarify causal relationships, validate microbial biomarkers, and translate preclinical findings into clinical applications. Addressing the gut-breast axis may offer transformative potential for precision oncology in obesity-driven BC.

Humans↗

PubMed2026

Targeting USP22 reprograms the tumor microenvironment and sensitizes KRAS/p53-driven lung cancer to anti-PD-1 immunotherapy.

RATIONALE: Ubiquitin-specific peptidase 22 (USP22), a deubiquitinase and component of the "Death-from-Cancer" 11-gene signature, is overexpressed in multiple malignancies and linked to recurrence, therapy resistance, and poor prognosis. Its role in KRAS/p53-driven lung cancer and the response to immune checkpoint inhibitors (ICIs) remains poorly defined. Here, we investigated USP22 as a potential therapeutic target in KRAS/p53-driven lung cancer. METHODS: A conditional Usp22 knockout (Usp22-KO) was generated in the KRASG12D; p53-/- (KP) mouse model. Cancer progression was monitored by micro-computed tomography (micro-CT). Multiplex immunofluorescence (mIF), RNA sequencing, and spatial transcriptomics profiled cancer and tumor microenvironment (TME) changes. Responses to anti-PD-1/PD-L1 therapies were compared between KP and Usp22-KO KP (KPU-) lung cancers. RESULTS: USP22 was highly expressed in early-stage KRAS/p53-driven mouse lung cancers and strongly correlated with proliferation marker Ki67. Usp22 deletion suppressed cancer growth, prolonged survival, and promoted cancer differentiation. Spatial transcriptomics and mIF revealed reduced CD206+ M2 macrophages, myeloid-derived suppressor cells (MDSCs), TGF-β1, and angiogenesis, along with increased functional CD8+ T cells. Mechanistically, USP22 regulated gene expression and protein stability, reducing c-Myc, PD-L1, TGF-β1, and SPARC upon Usp22 loss. Compared with KP cancer, KPU- and SPARC-knockdown KP cancers showed reduced macrophage chemotaxis and impaired basal- and TGF-β1-induced M2 polarization of RAW264.7 cells, suggesting that TGF-β1 and SPARC downregulation partially contributes to decreased M2 macrophage infiltration in KPU- cancers. Notably, Usp22 loss enhanced the efficacy of anti-PD-L1 and anti-PD-1 therapies in orthotopic and subcutaneous KP lung cancer models, respectively. USP22 and SPARC expression were also strongly correlated in human lung cancers. CONCLUSIONS: USP22 promotes progression and immune evasion in KRAS/p53-driven lung cancer. Targeting USP22 reprograms the TME, suppresses oncogenic signaling, and sensitizes tumors to ICI, establishing USP22 as a promising therapeutic target.

Animals↗

PubMed2026

Myeloid-Mediated Immunoregulation and Resistance to Immune Checkpoint Inhibitor Therapy Across Squamous Cell Carcinomas: Mechanisms and Reprogramming Strategies.

Immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 have improved outcomes across squamous cell carcinomas (SCCs) of the head and neck, lung, esophagus, and skin, yet durable responses remain confined to a subset of patients in every subtype. Objective response rates vary substantially across SCCs despite overlapping genomic alterations, comparable tumor mutational burden, and high PD-L1 expression, indicating that tumor-intrinsic biomarkers alone do not explain this variability. Growing evidence points to the tumor immune microenvironment, and in particular the myeloid compartment, as a critical determinant of immunotherapy responsiveness. In this review, we synthesize current evidence on myeloid-mediated immune regulation across SCC subtypes, focusing on tumor-associated macrophages, myeloid-derived suppressor cells/tumor-associated neutrophils, and dendritic cells, and the mechanisms by which these populations impair antigen presentation, restrict T cell infiltration, and sustain immunologically "cold" tumor states. We further examine therapeutic strategies aimed at reprogramming rather than simply depleting suppressive myeloid populations, including radiation therapy, STING agonism, and myeloid-targeted agents (CSF1R, PI3Kγ, and CXCR2 inhibition), each of which has shown encouraging preclinical and early clinical activity in combination with ICI. Collectively, this evidence supports a model in which the myeloid compartment functions as an actionable, convergent determinant of ICI resistance across SCC subtypes, rather than merely a passive biomarker. We propose that through the integration of spatial and single-cell profiling of myeloid states with clinical history it will be possible to predict response to immune checkpoint therapy and personalize myeloid-directed combination strategies, though the specific biomarkers needed to match individual patients to a given myeloid-targeted approach remain to be defined. We further discuss the toxicity considerations associated with both immune checkpoint blockade and radiation-based combination approaches, the early-phase status of most myeloid-targeted agents currently in clinical development, and the extent to which mechanistic insight, derived predominantly from HNSCC, generalizes to squamous cell carcinomas arising at other anatomic sites.

dendritic cells↗