Wei Lu

Cancer-associated hematopoietic abnormalities contribute to systemic immunosuppression. However, whether tumors can initiate localized extramedullary hematopoiesis to suppress antitumor immunity remains unclear. In this study, we identify a distinct form of hepatic hematopoiesis driven by liver metastasis–associated hematopoietic stem cells (LM-HSCs). Liver metastases establish ectopic periportal hematopoietic niches that recruit bone marrow HSCs through Kupffer cell–dependent C-C motif chemokine receptor 1 (CCR1) signaling. Although LM-HSCs retain self-renewal and multipotency, cAMP response element–binding protein (CREB) activation skews their differentiation toward the myeloid lineage, particularly annexin A1–positive (ANXA1 ⁺ ) immature neutrophils. These neutrophils produce glucocorticoids, which activate glucocorticoid receptor signaling in a paracrine manner and induce immune checkpoint receptor expression and functional anergy in CD8 ⁺ T and natural killer cells. Collectively, these findings suggest that liver metastases reprograms hepatic hematopoiesis to promote immunosuppression.

The clinical success of T-cell-based immunotherapies has transformed oncology, yet tumor immune evasion remains a formidable barrier. In this review, we delineate the developmental and molecular landscapes that shape antitumor T-cell immunity. Following a brief overview of CD4 ⁺ helper T-cell contributions, we focus primarily on CD8 ⁺ cytotoxic lineages. Rather than a passive loss of effector function, CD8 ⁺ T-cell exhaustion is increasingly recognized as functional attrition and profound oligoclonality. In the immunosuppressive tumor microenvironment (TME), unremitting antigenic pressure drives an iterative selection process that` narrows a highly diverse T-cell pool into a constricted, oligoclonal population, a phenomenon termed “clonal contraction”. We expand the conceptual scale of T-cell clonal selection during the immune response, tracing this clonal evolution from early thymic selection and primary antigen priming to exhaustive terminal differentiation. We further propose a structural model demonstrating how the biophysical constraints of a fixed T-cell receptor (TCR) repertoire create a profound imbalance against rapidly diversifying tumor antigens. Within this framework, we highlight tissue-resident memory (Trm) as a crucial spatial reservoir that safeguards the host against the depletion of functional clones. Finally, we contextualize the therapeutic paradigm of immune checkpoint inhibition (ICI) and note that, under some circumstances, durable clinical efficacy can be driven by systemic “clonal replacement”. Ultimately, we argue that next-generation T-cell-based immunotherapies may shift `from attempting only to reverse functional exhaustion to actively engineering continuous clonal selection and preserving TCR repertoire diversity.

Emerging evidence highlights defects in DNA damage repair as critical modulators of tumor immunogenicity, yet, the mechanistic interplay between repair pathway dynamics and immune checkpoint inhibitor efficacy remains elusive. We identify exonuclease 1 (EXO1), a dual-function nuclease that functions in homologous recombination (HR) and mismatch repair (MMR), as a pivotal orchestrator of immunogenomic regulation in lung adenocarcinoma (LUAD). An integrated multi-omics analysis of LUAD cohorts in The Cancer Genome Atlas revealed that EXO1 overexpression is strongly associated with genomic instability and poor prognosis (hazard ratio =1.047, P=3.72×10⁻⁸). Functional studies in syngeneic murine models revealed that Exo1 ablation induces a “controlled genomic chaos” state, delaying HR-mediated fidelity (P+ T cells (CD39⁺ Granzyme B⁺; PExo1-deficient tumors exhibited 100% objective response to anti-programmed death receptor-1 (PD-1) therapy versus 40% in controls (PExo1 suppression spared MMR functionality while preferentially engaging non-homologous end joining-driven immunoediting. Our work deciphers DNA damage repair-immune crosstalk governed by biased repair kinetics, nominating Exo1 abrogation as a transformative strategy to overcome immune checkpoint inhibitor resistance in genomically stable tumors.

CD8⁺ T cells are the primary killer cells that fight infections and malignantly transformed cells in vivo. In response to various stimuli, activated CD8⁺ T cells differentiate into effector and memory CD8⁺ T cells, which eliminate target cells and provide long-term protective immunity, respectively. Aberrant CD8⁺ T cell function induced by aging can lead to immune-related disorders. Both endogenous and exogenous stress affect the aging process of CD8⁺ T cells. CD8⁺ T cell aging results in cell senescence, characterized by disrupted cell proliferation, and impairs many other CD8⁺ T cell-related immune responses. It is now well-established that the aging of immune cells, including CD8⁺ T cells, exacerbates the body’s inflammation and promotes cell senescence in distant tissues, thereby accelerating the onset and progression of age-related diseases. Therefore, clarifying the genetic characteristics, molecular mechanisms, and specific markers of aged CD8⁺ T cells is crucial for delivering precise and effective therapeutic interventions for age-related diseases, particularly those induced by CD8⁺ T cell aging.

Glucocorticoid drugs (GCs), while effective in systemic lupus erythematosus (SLE), cause severe systemic side effects due to lack of tissue-specificity. To overcome this bottleneck, we developed a CD74-directed antibody–drug conjugate (Bud-ADC) to deliver budesonide, a potent GC drug, selectively to target CD74-expressing immune cells (e.g., B cells, dendritic cells), which play an important role in SLE pathogenesis. Bud-ADC combines a cross-species anti-CD74 antibody with budesonide via a cleavable linker, enabling immunosuppression on targeted cells. In vitro, Bud-ADC selectively inhibited CD74-high immune cell activation and cytokine production. In two SLE mouse models, Bud-ADC significantly alleviated disease hallmarks—reducing autoantibodies, splenomegaly, and kidney damage—while showing superior efficacy to free budesonide at equivalent doses. The therapeutic effects involved both direct targeting of CD74-high immune cells and indirect modulation of T cell responses despite low CD74 expression. This study establishes CD74-targeted ADC as a novel strategy to enhance GC efficacy in SLE, aiming at minimizing off-target toxicity while maintaining broad immunosuppressive activity. The translatable design supports further preclinical and clinical development for autoimmune diseases.

Chronic stimulation in the tumor microenvironment can induce exhausted CD8⁺ T (T_ex) cells that have limited tumoricidal activity. Here, we show an inverse correlation between signal strength and T_ex cell differentiation by using patient-derived mutations in the T cell receptor (TCR)-signaling protein CARD11. Strong TCR signaling of the E134G mutant inhibits T_ex cell differentiation and increases tumor growth. Conversely, reduced TCR signaling by the K215M mutant promotes T_ex cell differentiation with better tumor control. These effects are a result of a restrained tumor-specific TCR clonal repertoire of T_ex cells that reduces immunopathology but compromises tumoricidal activity. Mechanistically, CARD11 is a TCR signal-strength sensor, controlling the TCR repertoire of T_ex cells by regulating the trafficking and homeostasis of the TCR complex. Expanding the TCR repertoire during T_ex cell differentiation by fine-tuning the CARD11-mediated TCR signal strength reinvigorated antitumor function and indicates a strategy for improving cancer immunotherapy.

Background: Monocytes have been confirmed to increase in persistently food-allergic children. A phenomenon of innate immune memory, called trained immunity, has also been observed in monocytes from allergic children. However, the underlying mechanism remains poorly understood.Methods: We enrolled a cohort of HDM-allergic children alongside age-matched healthy controls and established an HDM-sensitized allergic mouse model. Flow cytometric analyses were conducted to quantify monocyte frequencies in clinical cohorts and experimental animals. We performed integrated transcriptomic profiling via RNA-seq combined with chromatin occupancy analysis using CUT&Tag technology in parallel human and murine samples to elucidate the molecular mechanisms.Results: In our study, we demonstrated a reduced H3K27me3 methylation level accompanied by an increased proportion and a proinflammatory transcriptional memory in monocytes from house dust mite (HDM)-allergic human subjects. The same transcriptional and epigenetic phenotype was also confirmed in HDM-sensitized mice. Finally, the administration of GSK-J4, which upregulates H3K27me3 level in murine monocytes, attenuated the inflammatory response in vitro and in vivo.Conclusions: Our study confirms that H3K27me3 methylation modulates the trained immunity in monocytes and regulates HDM-allergic diseases through an inflammatory-dependent mechanism.

Purpose Moesin (MSN) deficiency is a recently reported combined immunodeficiency, and few cases have been reported to date. We describe a Chinese patient with a novel mutation causing MSN deficiency and a novel phenotype. Methods Clinical and immunological data were collected. Whole-exome sequencing was performed to identify gene mutations. MSN protein expression and T cell proliferation and activation were determined by flow cytometry. Cell migration was confirmed with a Transwell assay. Autoantibody levels were analyzed using antigen microarrays. Results The patient was a 10-year-old boy who presented with recurrent fever, oral ulcers and dermatomyositis-like symptoms, such as periorbital edema, facial swelling, elevated creatine kinase levels, and abnormal electromyography and muscle biopsy results. Epstein–Barr virus (EBV) DNA was detected in the serum, cells and tissues of this patient. He further developed nasal-type NK/T-cell lymphoma. A novel hemizygous mutation (c.68 A > G, p.N23S) in the MSN gene was found. The immunological phenotype of this patient included persistent decreases in T and B lymphocyte counts but normal immunoglobulin IgG levels. The patient had attenuated MSN protein expression and impaired T-cell proliferation and migration. The proportions of Tfh cells and CD21^low B cells in the patient were higher than those in the controls. Moreover, 82 IgG and 102 IgM autoantibodies were more abundant in the patient than in the healthy controls. Conclusions The novel mutation N23S is pathogenic and leads to a severe clinical phenotype. EBV infection, tumor, and dermatomyositis-like autoimmune symptoms may be associated with MSN deficiency, further expanding the understanding of the disease.