Min Luo

The immunosuppressive tumor microenvironment remains a major obstacle to successful immunotherapy. Pathologically activated neutrophils, alternatively termed polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), drive tumor immune evasion primarily by inducing CD8⁺ T cell tolerance. While direct intercellular contact between neutrophils and CD8⁺ T cells is essential for immunosuppressive activity, the mechanisms mediating this interaction need deeper understanding. We previously reported that CD300ld is required for recruiting PMN-MDSCs into tumors, suppressing T cell activation. Here we show that CD300ld mediates neutrophil-driven contact-dependent suppression of cytotoxic CD8⁺ T cells by binding to phosphatidylserine (PS). Mice with mutant CD300ld lacking PS-binding capacity exhibit reduced immunosuppressive activity. Blockade of the CD300ld-PS interaction by neutralizing antibodies demonstrates therapeutic efficacy against established tumors and synergizes with anti-PD1. Our findings establish CD300ld-PS-mediated cell contact as a critical mechanism of neutrophil-driven immune evasion, revealing a targetable checkpoint pathway to overcome tumor immune resistance and improve immunotherapy outcomes.

Tumor cells are highly dependent on branched-chain amino acids, which can activate mechanistic target of rapamycin complex 1, but the downstream catabolite branched-chain α-keto acids (BCKAs) are not well studied in this context. Here, using clinical samples and genetically engineered mouse tumor models, we showed that tumor-derived BCKAs are secreted actively into the tumor microenvironment (TME) where they reprogram tumor-associated macrophages (TAMs) to promote tumor progression. Through genome-wide CRISPR screening, we identified Notch2 as a direct molecular target of BCKAs. BCKAs activate Notch signaling by binding to and stabilizing cleaved Notch2, functionally reprogramming TAMs and fostering an immunosuppressive TME. Mutation of the BCKA-binding site in Notch2 abolishes this effect in vivo. Together, these findings identify BCKAs as signaling metabolites that mediate tumor immunosuppression through direct sensing by Notch2.

Immune checkpoint blockade (ICB) therapy for many cancers remains limited in patients’ overall response rate. Discovery and development of more effective combinatorial approaches is urgent. Here, through CRISPR/Cas9 genetic screens, we identify DOT1L as a versatile epigenetic factor that functions to suppress tumor-intrinsic immunity through a dual mechanism. Depletion of DOT1L induces the expression of transposable elements and subsequent type I interferon (IFN) response, and meanwhile lowers ZEB1 levels to further unleash the expression of immune-related genes. In turn, we demonstrate that DOT1L loss or treatment with the clinical stage inhibitor EPZ-5676 sensitizes tumors to ICB with increased immune infiltration in mice. More importantly, EPZ-5676 treatment alone is sufficient to enhance antitumor immunity in humanized mice. TCGA data analysis reveals an inverse correlation between DOT1L expression and IFN signatures across multiple cancer types. These findings provide a rationale for targeting DOT1L to improve tumor immunogenicity and overcome immunotherapy resistance.

Respiratory viral infections, such as influenza and COVID-19, pose significant global health challenges. For patients with invasive pulmonary aspergillosis, a subsequent viral infection can lead to markedly worse clinical outcomes. Although amphotericin B (AmB) remains a cornerstone antifungal therapy, our investigation demonstrates that it paradoxically enhances the entry of influenza A virus and SARS-CoV-2. Mechanistically, AmB directly binds to and activates glucocerebrosidase, leading to ceramide accumulation and RAB7 upregulation in the late endosomes, thereby enhancing late endosomal maturation and fusion with viruses. In animal models, AmB treatment enhances viral infection in both influenza A virus–infected mice and SARS-CoV-2–challenged hamsters, resulting in accelerated weight loss, higher viral loads, and aggravated tissue damage. Consistently, in our propensity score-matched cohort of patients with culture-confirmed invasive pulmonary aspergillosis (2016–2025, n = 1,072), systemic use of AmB is associated with a significantly higher incidence of subsequent viral infection compared to other antifungals (21.55% vs. 7.76%, P = 0.003), which is further supported by multivariable analysis confirming AmB as an independent risk factor (adjusted OR = 3.45, 95% CI 2.20–5.41, P = 7.174 × 10 ^-8 ). In summary, our findings provide crucial clinical evidence to guide antifungal therapy and reveal glucocerebrosidase as a potential target for developing novel antiviral strategies.

Background: While cancer vaccines have demonstrated promising clinical potential, their therapeutic efficacy against advanced tumors remains suboptimal, highlighting the critical need to elucidate resistance mechanisms and develop targeted solutions. We previously developed a stimulator of interferon genes (STING)-activating PC7A nanovaccine that elicits strong antitumor efficacy in multiple tumor models. In this study, we systematically investigated the mechanisms mediating nanovaccine resistance and provided targeting approaches to overcome this therapeutic barrier. Methods: Vaccine efficacy at early stage and advanced-stage tumors was investigated in the B16-OVA melanoma model and TC-1 human papillomavirus-induced cancer model, with tumor microenvironment being comprehensively analyzed by flow cytometry. In a vaccine-resistant tumor, elevated immunosuppressive activity of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) was assessed through multi-analysis including surface marker staining, reverse transcription-quantitative PCR, and functional T cell-suppression assay. To investigate the CD300ld blockade strategy, we employed CD300ld-knockout (KO) mice for genetic ablation, or recombinant protein capable of competitive inhibition for pharmacological intervention. For clinical relevance assessment, we tested different cancer vaccine formulations at late-stage tumors in humanized-CD3000ld mice. Results: In contrast to early stage vaccination, PC7A nanovaccine administration at the late tumor stage exhibited minimal therapeutic effects on tumor progression, while concurrently increasing PMN-MDSC infiltration and enhancing their immunosuppressive activity. KO of CD300ld, a critical immune suppressor on PMN-MDSCs, abolished both PMN-MDSC recruitment and their T-cell suppressive function, restoring the antitumor efficacy of PC7A vaccine in multiple advanced tumor models. Furthermore, in wild-type and CD300ld humanized mouse models, competitive blockade of CD300ld using recombinant extracellular domain proteins overcame resistance of advanced tumors to different cancer vaccine formulations. Conclusion: Our results reveal that vaccination at the late tumor stage significantly augments the recruitment and immunosuppressive capacity of PMN-MDSCs, driving resistance of advanced tumors to cancer vaccines. The findings demonstrate PMN-MDSCs as critical mediators of vaccine resistance in advanced tumors and highlight modulation of PMN-MDSCs by CD300ld blockade as a promising strategy to enhance the therapeutic efficacy of cancer vaccines, particularly for patients with late-stage malignancies.

Introduction: Lupus nephritis (LN), a severe complication of systemic lupus erythematosus (SLE), is characterized by persistent immune dysregulation and glomerular injury predominantly driven by macrophage infiltration and type I interferon (IFN-I) signaling. Crosstalk between injured podocytes and infiltrating macrophages is increasingly recognized as a key contributor to LN progression; however, the molecular mediators and their corresponding receptors remain poorly defined. This study investigates whether ANGPTL3 upregulation in podocytes activates macrophages through MSR1 and drives interferon-biased inflammation in LN. Methods: We employed secretome-based protein-protein interaction screening to identify ANGPTL3 receptors. The ANGPTL3-MSR1 interaction was supported by co-immunoprecipitation. In vitro, bone marrow-derived macrophages (BMDMs) were stimulated with ANGPTL3-conditioned media, and gene expression was analyzed by RNA sequencing. MSR1 was silenced using siRNA. In vivo, a pristane-induced lupus mouse model was used to assess glomerular ANGPTL3/MSR1 expression, renal function, and macrophage infiltration. Clinical relevance was assessed using Nephroseq datasets and human LN kidney specimens. Results: ANGPTL3 was identified as an MSR1-interacting ligand through a cell-based membrane protein screening assay and further supported by co-immunoprecipitation. In vitro, ANGPTL3-conditioned media induced an interferon-dominant transcriptional response in BMDMs, including upregulation of Tnip3 and Isg20. These effects were attenuated upon MSR1 silencing, confirming receptor-dependent activation. Notably, ANGPTL3 had minimal effect on M1/M2 polarization markers, indicating selective regulation of interferon signaling. Analysis of Nephroseq datasets and LN biopsies demonstrated elevated ANGPTL3 and MSR1 expression, which correlated with histopathological severity. Single-cell RNA-seq confirmed MSR1 enrichment in glomerular macrophages. In vivo, pristane-induced lupus mice exhibited increased glomerular ANGPTL3, Synaptopodin loss, proteinuria, and colocalization of F4/80 and MSR1, supporting a pathogenic podocyte-macrophage axis. Conclusion: This study identifies the ANGPTL3-MSR1 axis as a critical pathway linking podocyte injury to macrophage-driven inflammation in LN, highlighting its therapeutic potential. Targeting this axis may disrupt maladaptive immune crosstalk, offering a novel strategy for LN management.

Personalized cancer vaccines elicit robust T cell immunity and anti-tumour potency, but identifying tumour-specific antigens remains challenging, severely constraining the therapeutic window. Biomimetic nanovaccines employing cancer cell membranes display inherent biocompatibility and stimulate T-cell responses against diverse tumour antigens, though tumours develop multiple mechanisms to reduce antigen presentation. Here we demonstrate a rapid and general strategy to fabricate personalized nanovaccines based on Antigen-Enriched tumor Cell Membranes (AECM) for early intervention. Interferon-γ potently stimulates antigen presentation across a broad range of cancer cell types. By coupling the generated AECM with PC7A adjuvant, a stimulator of interferon genes (STING)-activating polymer, the AECM@PC7A nanovaccine induces robust poly-neoepitopic T-cell responses even at low dosage, achieving significant tumour regression and metastasis inhibition in multiple murine cancer models. This anti-tumor response relies on MHC-I restricted antigen presentation and CD8⁺ T-cell activation, with dendritic cells presenting AECM antigens predominantly via cross-dressing to prime T-cells. AECM@PC7A exhibits remarkable anti-tumor efficacy when compared to vaccines with diverse formulations, and demonstrates therapeutic potential in post-surgical and humanized xenograft tumor models. This proof-of-concept study provides a promising universal avenue for the rapid development of personalized cancer vaccines applicable to early intervention for a broad range of patients.

Tumor-associated neutrophils (TANs) represent a significant barrier to the effectiveness of immune checkpoint blockade (ICB) therapy. A comprehensive understanding of TANs' regulatory mechanisms is therefore essential for predicting ICB efficacy and improving immunotherapy strategies. Our study reveals that MYO1F is selectively downregulated in neutrophils within both human cancers and murine tumor models, showing a negative correlation with ICB response. Mechanistically, MYO1F normally inhibits neutrophil immunosuppression and proliferation by restraining STAT3 activity. However, during tumorigenesis, tumor-derived TGF-β1 disrupts the binding of SPI1 to intron 8 of Myo1f via DNA methylation, thereby suppressing Myo1f transcription. The resultant decrease in MYO1F reprograms neutrophils into an immunosuppressive state through the STAT3-dependent signaling pathways. This immunosuppressive state further contributes to tumor microenvironment (TME) remodeling by inducing CTL exhaustion. These findings establish MYO1F as a critical regulator within TANs, highlighting its significant role in modulating ICB therapy efficacy.

The secretome is composed of cell surface membrane proteins and extracellular secreted proteins that are synthesized via secretory machinery, accounting for approximately one-third of human protein-encoding genes and playing central roles in cellular communication with the external environment. Secretome protein–protein interactions (SPPIs) mediate cell proliferation, apoptosis, and differentiation, as well as stimulus- or cell-specific responses that regulate a diverse range of biological processes. Aberrant SPPIs are associated with diseases including cancer, immune disorders, and illness caused by infectious pathogens. Identifying the receptor/ligand for a secretome protein or pathogen can be a challenging task, and many SPPIs remain obscure, with a large number of orphan receptors and ligands, as well as viruses with unknown host receptors, populating the SPPI network. In addition, proteins with known receptors/ligands may also interact with alternative uncharacterized partners and exert context-dependent effects. In the past few decades, multiple varied approaches have been developed to identify SPPIs, and these methods have broad applications in both basic and translational research. Here, we review and discuss the technologies for SPPI profiling and the application of these technologies in identifying novel targets for immunotherapy and anti-infectious agents.