Despite functional heterogeneity, the high frequency of intratumoral neutrophils predicts poor clinical outcomes. The tumor microenvironment reprograms neutrophils into immunosuppressive subsets that hinder anticancer immunity, thereby contributing to tumor growth and resistance to immunotherapies. However, the mechanisms underlying neutrophil reprogramming remain elusive. In this study, we report that the immunosuppressive ability of brain tumor–infiltrating neutrophils was restricted to a highly glycolytic and long-lived subset expressing CD71, which acquired immunosuppressive properties in response to hypoxia. Mechanistically, hypoxia boosted glucose metabolism in CD71+ neutrophils, leading to high lactate production. Lactate caused histone lactylation, which subsequently regulated arginase-1 expression, required for T-cell suppression. Targeting histone lactylation with the antiepileptic drug isosafrole blocked CD71+ neutrophil immunosuppressive ability, delayed tumor progression, and sensitized brain tumors to immunotherapy. A distinctive gene signature characterizing immunosuppressive CD71+ neutrophils correlated with adverse clinical outcomes across diverse human malignancies. This study identifies histone lactylation as a potential therapeutic target to counteract neutrophil-induced immunosuppression within tumors. Significance: Neutrophils are critical contributors to the immunosuppressive microenvironment that restricts the effects of promising immunotherapies in glioblastoma. Our study identifies hypoxia-driven histone lactylation as a potential target to block immunosuppressive neutrophils and boost the effects of immunotherapy in glioblastoma and in other cancer settings beyond brain tumors.

Blocking the Programmed Cell Death Protein 1 (PD-1)/programmed death ligand-1 (PD-L1) axis has demonstrated great efficacy in cancer immunotherapy treatment and remains the central modality of immune targeting. To support the rational and tailored use of these drugs, it is important to identify reliable biomarkers related to survival. The role of the soluble form of the PD-L1 (sPD-L1) as a prognostic biomarker related to survival in solid cancer patients treated with immunotherapy has not yet been consistently evaluated. A systematic literature search of original articles in PubMed, MEDLINE and Scopus was conducted. Studies reporting hazard ratios (HRs) with a 95% confidence interval (CI) or Kaplan–Meier curves or individual patient data for overall survival (OS) or progression-free survival (PFS) associated with baseline levels of sPD-L1 in cancer patients undergoing immunotherapy treatment were considered eligible. Twelve studies involving 1076 patients and different tumor types treated with immunotherapy were included in the analysis. High blood levels of sPD-L1 correlated with poorer OS and PFS in cancer patients treated with immunotherapy (HR = 1.49, 95%CI: 1.15, 1.93, p < 0.01, I² = 77% for OS; HR = 1.59, 95%CI: 1.20, 2.12, p < 0.01, I² = 82% for PFS). A subgroup analysis highlighted that high levels of sPD-L1 were associated with worse survival in patients affected by NSCLC (HR = 1.81 95%CI: 1.09–3.00, p = 0.02, I² = 83% for OS; HR = 2.18, 95%CI: 1.27–3.76, p < 0.01, I² = 88% for PFS). An HR > 1 indicated that patients with low levels of sPD-L1 have the highest rates of OS/PFS. In this meta-analysis, we clarified the role of sPD-L1 in different solid cancers treated exclusively with Immune checkpoint inhibitors (ICIs). sPD-L1 could represent a non-invasive biomarker that is easily dosable in the blood of patients. The pooled data from the selected studies showed that a high circulating concentration of sPD-L1 in cancer patients correlates with worse survival, suggesting that it may be a helpful prognostic biomarker for the selection of cancer patients before immunotherapy, thus improving the efficacy of ICIs and avoiding unnecessary treatment.

Cabozantinib (XL-184) is a multitarget tyrosine kinase inhibitor (TKI) targeting receptor tyrosine kinases (RTKs) involved in oncogenesis and angiogenesis. It is currently the standard therapy for medullary thyroid cancer (MTC), metastatic renal cell carcinoma (mRCC), and hepatocellular carcinoma (HCC). Combination of Cabozantinib with immunotherapy is now a standard treatment in metastatic renal cancer, and its efficacy is being tested in ongoing clinical trial in prostate cancer patients. Here, we report that Cabozantinib may exert an immunostimulatory role by inducing immunogenic stress of prostate cancer cells and directly modulating dendritic cells (DCs). Cabozantinib treatment arrested the cell cycle and triggered immunogenic cell death (ICD) in prostate cancer cells in vitro. Cabozantinib had a direct effect on DCs by the down-modulation of β-catenin and change in migratory and costimulatory phenotype of the DCs. These results may suggest possible immunomodulatory effects induced by Cabozantinib that could be exploited to optimize patient-tailored immunotherapeutic treatments.

Despite diagnostic and therapeutic improvements, glioblastoma (GB) remains one of the most threatening brain tumor in adults, underlining the urgent need of new therapeutic targets. Lectins are glycan-binding proteins that regulate several biological processes through the recognition of specific sugar motifs. Lectins and their ligands are found on immune cells, endothelial cells and, also, tumor cells, pointing out a strong correlation among immunity, tumor microenvironment and vascularization. In GB, altered glycans and lectins contribute to tumor progression and immune evasion, shaping the tumor-immune landscape promoting immunosuppressive cell subsets, such as myeloid-derived suppressor cells (MDSCs) and M2-macrophages, and affecting immunoeffector populations, such as CD8⁺ T cells and dendritic cells (DCs). Here, we discuss the latest knowledge on the immune cells, immune related lectin receptors (C-type lectins, Siglecs, galectins) and changes in glycosylation that are involved in immunosuppressive mechanisms in GB, highlighting their interest as possible novel therapeutical targets.

Pembrolizumab, an anti-PD-1 antibody, has been approved as first-line treatment for recurrent or metastatic head and neck squamous cell carcinoma ((R/M) HNSCC). However, only a minority of patients benefit from immunotherapy, which highlights the need to identify novel biomarkers to optimize treatment strategies. CD137⁺ T cells have been identified as tumour-specific T cells correlated with immunotherapy responses in several solid tumours. In this study, we investigated the role of circulating CD137⁺ T cells in (R/M) HNSCC patients undergoing pembrolizumab treatment. PBMCs obtained from 40 (R/M) HNSCC patients with a PD-L1 combined positive score (CPS) ≥1 were analysed at baseline via cytofluorimetry for the expression of CD137, and it was found that the percentage of CD3⁺CD137⁺ cells is correlated with the clinical benefit rate (CBR), PFS, and OS. The results show that levels of circulating CD137⁺ T cells are significantly higher in responder patients than in non-responders (p = 0.03). Moreover, patients with CD3⁺CD137⁺ percentage ≥1.65% had prolonged OS (p = 0.02) and PFS (p = 0.02). Multivariate analysis, on a combination of biological and clinical parameters, showed that high levels of CD3⁺CD137⁺ cells (≥1.65%) and performance status (PS) = 0 are independent prognostic factors of PFS (CD137⁺ T cells, p = 0.007; PS, p = 0.002) and OS (CD137⁺ T cells, p = 0.006; PS, p = 0.001). Our results suggest that levels of circulating CD137⁺ T cells could serve as biomarkers for predicting the response of (R/M) HNSCC patients to pembrolizumab treatment, thus contributing to the success of anti-cancer treatment.

Background: Overwhelming presence of immunoregulatory myeloid cells and dysfunctional T cells is a major barrier to effective immunotherapies in glioblastoma (GBM). Therapeutic strategies that simultaneously address myeloid-driven immunosuppression and impaired T cell function are therefore needed to restore antitumor immunity in GBM. Methods: We employed single-cell RNA sequencing, immunophenotyping, and functional analyses in an orthotopic murine GBM model (SB28) to investigate how hypoxia shapes the tumor immune microenvironment and limits CD8+ T cell responses. Pharmacologic hypoxia modulation using low-dose axitinib was combined with therapeutic intervention targeting CD137 in two GBM models (SB28, CT2A). Results: Monocyte-derived macrophages (MDMs) and neutrophils constitute the most abundant and functionally immunosuppressive myeloid subsets within the GBM TME. Hypoxia reprogrammed MDMs and neutrophils into immunosuppressive cells, limiting the expansion of CD8+ T cells. Low-dose axitinib reduced intratumoral hypoxia, leading to altered glucose uptake and histone lactylation in MDMs and neutrophils, thereby impairing their immunosuppressive function and promoting the expansion of intratumoral PD-1+CD137+CD8+ T cells, specifically in the SB28 model. CD137 is largely expressed by effector-like exhausted CD8+ T cell subsets (EX-eff). Agonistic targeting of CD137, in combination with axitinib, robustly expanded EX-eff, which was accompanied by durable tumor regression, immunological memory, and long-term survival. Additionally, the abundance of PD-1+CD137+CD8+ T cells correlated with improved disease-free survival in patients with GBM. Conclusion: Together, these findings establish a rationale for a combinatorial strategy that couples myeloid cells targeting and CD8+ T cell activation to overcome immunotherapy resistance in GBM.