Xuetao Cao

T cell exhaustion within the tumor microenvironment poses a major barrier to effective cancer immunotherapy, yet the epigenetic mechanisms that preserve functional states of tumor-infiltrating T cells remain incompletely understood. Here, using an in vivo CRISPR screen, we identify heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2B1) as a regulator of CD8+ T cell fitness. Transcriptomic analyses of cancer patient cohorts reveal that hnRNPA2B1 is preferentially enriched in a proliferative, intermediate exhausted T cell subset associated with favorable clinical outcomes. Genetic ablation of hnRNPA2B1 in CD8+ T cells accelerates terminal exhaustion, impairs antitumor immunity, and diminishes responsiveness to immune checkpoint blockade. Mechanistically, hnRNPA2B1 forms nuclear puncta and stabilizes RNAs involved in chromatin organization, thereby maintaining chromatin accessibility that restrains exhaustion-associated programs while preserving proliferative and cytotoxic potential. Together, these findings establish hnRNPA2B1 as an RNA-mediated epigenetic regulator sustaining functional exhausted T cell states in tumors.

T cell dysfunction critically limits the efficacy of T cell–based immunotherapies in solid tumors, yet the intrinsic regulators of T cell dysfunction remain incompletely understood. Through an in vivo genome-wide CRISPR screen in tumor-infiltrating CD8 ⁺ T cells, we identified Forkhead Box R1 (FOXR1) as a potent transcriptional suppressor of CD8 ⁺ T cell effector functions. Genetic ablation of FOXR1 significantly enhanced cytokine production and cytotoxic capacity in both murine and human CD8 ⁺ T cells, whereas its overexpression impaired T cell activation and effector molecule expression. Mechanistically, multiomics integration of RNA-seq, CUT&Tag-seq, and ATAC-seq revealed that FOXR1 binds directly to promoter regions of key effector genes, including IL2, GZMB, and PRF1 , and represses their expression. Importantly, FOXR1 deletion in human anti-CD19 CAR T cells improved their efficacy against solid tumors, demonstrating that FOXR1 is a checkpoint of T cell effector function and targeting FOXR1 is a promising strategy to enhance CAR T cell efficacy against solid tumors.

Much attention has focused on commensal bacteria in health and disease, but the role of commensal viruses is largely unexplored. Although commensal viruses are suggested in some organs such as intestine to maintain tissue homeostasis, it is unknown whether they participate in the physiology or pathology of nose, which directly contacts outer environment. Here, we focused on nasal commensal viruses in the development of allergic rhinitis (AR), a global health problem affecting 20% to 30% of the population, and found that clearance of nasal commensal viruses using ribavirin alleviated AR symptoms, suggesting that these viruses contribute to AR pathogenesis. Mechanistically, nasal commensal viruses, recognized by innate sensors, initiated the production of type I interferon, recruiting and generating a population of interferon-induced neutrophils in the nasal cavity, which released neutrophil extracellular traps (NETs) to promote AR. Most importantly, to verify whether clearing nasal commensal viruses could treat AR patients clinically, we performed a randomized, double-blind, placebo-controlled, phase 2 clinical trial (Chinese Clinical Trial Registry identifier: www.chictr.org.cn ChiCTR2400082642) to explore the efficacy and safety of ribavirin spray in treating AR patients, and found that the patients of ribavirin group experienced significantly reduced nasal commensal viruses and alleviated symptoms as compared to the placebo group, determining the therapeutic efficacy of ribavirin spray. Thus, we suggest a new mechanism for AR and a new approach for treating AR patients.

Uncovering novel targets that synergize with immune checkpoint blockade (ICB) is an urgent clinical priority. While cancer cell‐intrinsic CD28 facilitates immune escape by functioning as a non‐classical RNA‐binding protein to stabilize CD274 (PD‐L1) mRNA, inhibiting this pathway in cancer cells without impairing essential T cell CD28 costimulation remains a major structural challenge. Here, we report the development of a 16:0 LPC‐modified SM102‐based lipid nanoparticle (LPC‐LNP) that exploits altered tumor lipid metabolism for highly selective cancer cell transfection. By leveraging elevated lysophosphatidylcholine acyltransferase (LPCAT) uptake mechanisms inherent to malignant cells, LPC‐LNPs efficiently deliver Cd28 small interfering RNA directly to tumor cells while strictly avoiding T cell sequestration. In vivo administration of LPC‐LNP‐Cd28 successfully knocked down 80% of cancer cell CD28, substantially reduced PD‐L1 expression, and circumvented the off‐target immunosuppression observed with commercial lipid formulations. Consequently, targeted Cd28 silencing reshapes the immunosuppressive tumor microenvironment, augmenting twofold CD8 ⁺ T cell infiltration and dendritic cell activation to extend survival in murine breast and lung cancer models to 1.3–1.5 folds. Furthermore, the combined use of LPC‐LNP‐Cd28 effectively eradicates resistance to anti‐PD‐1 therapy. This study provides a highly translatable, cancer‐specific nanomedicine platform, confirming that selectively antagonizing tumor‐intrinsic CD28 holds profound promise for advanced cancer immunotherapy.

Elucidating tumor-intrinsic mechanisms orchestrating immunosuppressive tumor microenvironment (TME) and cancer immunoevasion is essential for overcoming cancer immunotherapy resistance and developing novel therapeutic strategies. WDR82, a member of the WD-40 protein family, exhibits context-dependent regulation of cancer with undefined role in breast cancer and immunosuppressive TME. Here we identify WDR82 as a critical tumor suppressor governing immune surveillance by restraining the ERK-chemokine-neutrophil axis. WDR82 expression is downregulated in human breast cancer and correlates with poor prognosis. Although WDR82 promotes tumor cell proliferation in vitro, it suppresses tumor growth in vivo exclusively in immunocompetent hosts by enhancing neutrophil infiltration and CD8⁺ T cell exhaustion, creating an immunosuppressive TME. Neutrophil depletion abolishes WDR82's tumor-suppressive effect, confirming the functional dependency on this axis. Mechanistically, WDR82 directly binds MEK1/2 to disassemble c-RAF-MEK binding and inactivate ERK signaling. Wdr82 deletion restores ERK-dependent tumor cell CXCL2 and CXCL7 production to promote CXCR2-mediated neutrophil recruitment in the TME. Importantly, intratumoral WDR82-expressing adenovirus delivery reverses neutrophil accumulation and T cell exhaustion, suppressing tumor progression. Our findings uncover a previously unrecognized mechanism by which WDR82 suppresses MEK-ERK signaling, ERK-dependent chemokines production and neutrophil infiltration, consequently relieving immunosuppressive TME. This work establishes a promising therapeutic strategy for breast cancer.

The rapid induction of type I interferons (IFN-I) by innate signaling is indispensable for host defense; however, its uncontrolled expression invariably leads to autoimmune diseases. Here, we reveal that the E3 ubiquitin ligase UHRF2 functions as a highly specific epigenetic repressor of IFN-I gene transcription. During viral infection, activated TBK1 undergoes nuclear translocation, where it is hijacked by UHRF2 to achieve gene-specific targeting at IFN-I loci. Upon recruitment to IFN-I loci, UHRF2 physically interacts with histone deacetylase 1 (HDAC1), catalyzes atypical K29-linked polyubiquitination and prevents HDAC1 from degradation. This stabilized UHRF2-HDAC1 complex actively erases the lactylation of histone H4 at lysine 12 (H4K12la), thereby silencing IFN-I transcription. To mount an effective initial antiviral response, IFN-I signaling feedback transiently downregulates UHRF2 expression. Consequently, UHRF2-deficient mice exhibit profound resistance to lethal virus infection in vivo due to IFN-I overproduction. These findings uncover a highly coordinated mechanism wherein nuclear TBK1, UHRF2, and HDAC1 converge to epigenetically regulate immune homeostasis through histone delactylation, identifying UHRF2 as a potential therapeutic target for virus infection or autoimmune diseases.

Dendritic cells (DC) dysfunction impedes antitumor immunity, so understanding intrinsic regulators of DC antigen presentation and the resulting activation of antitumor CD8⁺ T cells could benefit therapy. Here, we use a genome-wide CRISPR screen for antigen presentation-regulating genes in DCs, and identify estrogen receptor α (ERα) as an intrinsic checkpoint inhibiting antigen cross-presentation. ERα genomic deficiency or pharmacological degradation enhances antigen presentation and CD8⁺ T cell priming in mouse and human DCs. Mechanistically, independently of canonical estrogen signaling, ERα sustains Galectin-3-mediated recruitment of CHMP4b to damaged phagosomes, thereby facilitating ESCRT-III-mediated membrane repair and restricting cytosolic antigen translocation. In vivo, ERα-deficient or ERα-degraded DC vaccines expand tumor-specific CD8⁺ T cells to suppress tumor growth in mice bearing subcutaneous cancers. In vitro, FDA-approved ERα antagonists enhance human DC-mediated activation of antigen-specific human CD8⁺ T cells. Our work thus uncovers a non-canonical role of ERα in phagosome integrity as a checkpoint for antigen cross-presentation in DCs, and implicates ERα-targeted DC vaccines as a potential immunotherapeutic strategy.

The discovery and investigation of Toll-like receptors (TLRs) has fundamentally reshaped our understanding of innate immunity and inflammation over the past four decades. These pivotal pattern-recognition receptors play a canonical role as sentinels that detect pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). In addition, TLR signaling is subject to exquisite multilayered regulation to prevent excessive inflammation and maintain immune homeostasis. Such regulation includes posttranslational modifications, epigenetic reprogramming, metabolic rewiring, and dynamic assembly of signaling condensates. This review comprehensively summarizes the intrinsic regulatory networks and tissue-microenvironment crosstalk that fine-tune TLR responses. We highlight the central roles of TLR signaling in infection, autoimmunity, cancer, inflammaging, cardiovascular diseases, and neurodegenerative disorders, underscoring how dysregulation drives pathology. Finally, we examine recent analyses and future prospects for pharmacological modulation of TLR pathways with agonists or antagonists as a promising therapeutic strategy for a broad spectrum of inflammatory and immune-mediated diseases. By bridging foundational mechanisms with clinical insights, this article illustrates how TLR research continues to illuminate immune regulation and offers novel avenues for targeted immunotherapy.