Neutrophils are increasingly recognized as functionally versatile immune cells, with tissue-specific phenotypes that extend beyond their classical role in acute inflammation. In osteoarthritis (OA), neutrophils are abundant in synovial fluid (SF), which has been linked to worse symptoms. Here, we characterized neutrophils in OA IFP and identified a distinct population of HLA-DR+ neutrophils enriched in OA IFP. Sorted IFP HLA-DR+ neutrophils induced the proliferation of autologous CD3+ T cells, supporting their role in antigen presentation. Proteomic profiling of OA IFP revealed the upregulation of metabolic and enzymatic activities as well as the downregulation of apoptotic and enzyme inhibition pathways, consistent with the increased fibrosis and neovascularization observed histologically. Collectively, our findings expand the functional scope of neutrophils in arthritic diseases, further establishing their potential in antigen presentation, and position the IFP as a previously underappreciated, immunologically active niche in OA pathogenesis.
© 2026 The Author(s).

The mechanisms mediating elite and persistent HIV control in people living with HIV (PLHIV) are only partially understood and largely attributed to adaptive T cell responses, but whether innate immunity also contributes remains unclear. Using samples from the 2000HIV study, we examined the transcriptional and functional profiles of monocytes from spontaneous HIV controllers and normal progressors on long-term antiretroviral therapy. HIV controllers displayed enhanced cytokine production after bacterial and viral stimulation, alongside antiviral and interferon-inducible transcriptional signatures and reduced inflammatory gene expression. Persistent controllers further showed increased capacity for trained immunity, with H3K4me3 profiling indicating the epigenetic priming of innate immune genes. Remarkably, relatives of persistent controllers also exhibited stronger innate and trained immune responses than relatives of normal progressors. These findings suggest that robust innate immunity, particularly monocyte function, may precede infection and contribute to sustained HIV control, offering new avenues for therapies that induce similar innate antiviral responses.
© 2026 The Authors.

The clearance of dying cells by phagocytes (efferocytosis) is important for maintenance of tissue homeostasis and the active repression of inflammatory responses but can promote an immunosuppressive tumor microenvironment. Here we show that Notch signaling is suppressed actively during efferocytosis and that activation of this pathway by ectopic expression of the Notch intracellular domain in myeloid cells improves anticancer immunity in mice. Contact with dead cells or IgG-coated surfaces induces the activation of an integrin barrier that excludes Notch from the contact site to prevent it signaling. The formation of this active integrin barrier requires the Rubicon-VPS34 complex, which recruits phospholipase D (PLD) to regulate integrin activation. Ablation of Rubicon in the host or inhibition of PLD increases Notch activation during efferocytosis and improves anticancer immunity in a manner dependent on Notch signaling. These findings identify a regulatory mechanism that restricts Notch signaling during efferocytosis.
© 2026. The Author(s).

Sequential immunization is a promising approach to elicit broadly neutralizing antibodies (bNAbs) against the HIV-1 Envelope (Env). However, available protocols are inefficient and involve multiple immunizations over long periods of time. Here, we present WIN332, a new engineered Env immunogen that induces a new class of Asn332-glycan-independent antibodies to the conserved V3-glycan epitope of Env with low inhibitory activity indicative of a neutralization activity after a single bolus immunization in nonhuman primates. WIN332 binds to precursors of canonical human Asn332-glycan-dependent (type-I) V3-glycan bNAbs but also of a first-of-its-class Asn332-glycan-independent (type-II) V3-glycan bNAb. A single immunization elicits low inhibitory serum and monoclonal antibodies that are boosted and affinity matured with a heterologous immunogen. Electron microscopy polyclonal epitope mapping analysis of serum antibodies, antibody cloning and cryogenic electron microscopy analysis reveals that WIN332 elicits Asn332-glycan-independent antibodies with striking sequence and binding similarities with the most potent human type-I and type-II V3-glycan bNAbs. Thus, WIN332 is a promising vaccine candidate to streamline V3-glycan bNAb elicitation.
© 2026. The Author(s).

Advanced renal cell carcinoma (RCC) is commonly treated with immune checkpoint inhibitor (ICI)-based therapies. However, patient responses vary, and predictive biomarkers remain limited. Here, we demonstrate that Schlafen 11 (SLFN11), which has emerged as an important gene in immunity and drug response, acts as a key enhancer of antitumor immunity in advanced RCC.
We analyzed transcriptome data from in-house and public RCC patient cohorts to evaluate associations between SLFN11 expression, clinical outcomes, and immune contexture. Transcriptome profiling of RCC cell lines was performed to identify SLFN11-regulated cytokines. Functional assays included co-culture of wild-type or SLFN11-knockout RCC cells with M0 macrophages, immature macrophages, followed by cytokine quantification and phenotypic analyses. Multiplex immunofluorescence staining was applied to formalin-fixed paraffin-embedded samples from ICI-treated patients to validate immune cell infiltration in the tumor microenvironment.
Clinically, patients with SLFN11-high RCC treated with ICI-based regimen showed significantly prolonged progression-free survival in both our cohort and public datasets. SLFN11-high RCC tumors exhibited increased infiltration of anti-tumoral M1 macrophages and up-regulation of immune-related pathways compared to SLFN11-low tumors. Mechanistically, transcriptome as well as proteome analysis revealed that, in RCC cells, SLFN11 significantly up-regulated the expression of colony stimulating factor 2 (CSF2) encoding granulocyte-macrophage colony-stimulating factor (GM-CSF), which promotes polarization from M0 macrophages to M1 macrophages. Consequently, SLFN11-positive RCC cells co-cultured with M0 macrophages secreted significantly higher levels of GM-CSF than SLFN11-negative cells and promoted M1 macrophage differentiation. Consistently, multiplex immunofluorescence staining of RCC patient sample analysis confirmed that the number of M1 macrophages was significantly higher in the tumor microenvironment of SLFN11-high tumor than in SLFN11-low tumor.
SLFN11 enhances antitumor immunity in RCC by increasing GM-CSF secretion and activating M1 macrophages, potentially improving ICI efficacy.
Copyright © 2026 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.