The interplay between cellular metabolism and immune regulation is central to immune function and disease progression, revealing notable therapeutic opportunities. Upon activation, immune cells undergo metabolic reprogramming to meet heightened demands for energy and biosynthesis, reshaping regulatory networks across epigenomic, transcriptomic, and proteomic layers. Metabolite-derived posttranslational modifications (PTMs) serve as pivotal mechanisms integrating metabolic intermediates with immune signaling pathways. Beyond classical acetylation, diverse nonacetyl PTMs—including lactylation, succinylation, malonylation, palmitoylation, and myristoylation—modify histone and nonhistone proteins, regulating gene expression, protein stability, subcellular localization, enzymatic activity, and protein-protein interactions. Advances in mass spectrometry and bioinformatics now enable precise characterization of these PTMs, uncovering their broad roles in immune regulation. This review summarizes current progress in immunometabolism and explores future directions such as mechanistic studies, combination strategies, and clinical applications. Metabolite-driven PTMs critically connect metabolism to immune regulation, suggesting promising therapeutic approaches for cancer, autoimmune disorders, and inflammatory diseases.

Transformation to aggressive disease histologies generates formidable clinical challenges across cancers, but biological insights remain few. We modeled the genetic heterogeneity of chronic lymphocytic leukemia (CLL) through multiplexed in vivo CRISPR-Cas9 B-cell editing of recurrent CLL loss-of-function drivers in mice and recapitulated the process of transformation from indolent CLL into large cell lymphoma [i.e., Richter syndrome (RS)]. Evolutionary trajectories of 64 mice carrying diverse combinatorial gene assortments revealed coselection of mutations in Trp53, Mga, and Chd2 and the dual impact of clonal Mga/Chd2 mutations on E2F/MYC and interferon signaling dysregulation. Comparative human and murine RS analyses demonstrated tonic PI3K signaling as a key feature of transformed disease, with constitutive activation of the AKT and S6 kinases, downmodulation of the PTEN phosphatase, and convergent activation of MYC/PI3K transcriptional programs underlying enhanced sensitivity to MYC/mTOR/PI3K inhibition. This robust experimental system presents a unique framework to study lymphoid biology and therapy. Significance: Mouse models reflective of the genetic complexity and heterogeneity of human tumors remain few, including those able to recapitulate transformation to aggressive disease histologies. Herein, we model CLL transformation into RS through multiplexed in vivo gene editing, providing key insight into the pathophysiology and therapeutic vulnerabilities of transformed disease. This article is highlighted in the In This Issue feature, p. 101

The link between viruses and cancer has intrigued scientists for decades. Certain viruses have been shown to be vital in the development of various cancers by integrating viral DNA into the host genome and activating viral oncogenes. These viruses include the Human Papillomavirus (HPV), Hepatitis B and C Viruses (HBV and HCV), Epstein-Barr Virus (EBV), and Human T-Cell Leukemia Virus (HTLV-1), which are all linked to the development of a myriad of human cancers. Third-generation sequencing technologies have revolutionized our ability to study viral integration events at unprecedented resolution in recent years. They offer long sequencing capabilities along with the ability to map viral integration sites, assess host gene expression, and track clonal evolution in cancer cells. Recently, researchers have been exploring the application of Oxford Nanopore Technologies (ONT) nanopore sequencing and Pacific BioSciences (PacBio) single-molecule real-time (SMRT) sequencing in cancer research. As viral integration is crucial to the development of cancer via viruses, third-generation sequencing would provide a novel approach to studying the relationship interlinking viral oncogenes, viruses, and cancer. This review article explores the molecular mechanisms underlying viral oncogenesis, the role of viruses in cancer development, and the impact of third-generation sequencing on our understanding of viral integration into the human genome.

Background: The accurate etiology of mitral valve aneurysm (MVA) formation is not completely understood, and the most effective management approach for this condition remains controversial.Methods: We retrospectively analyzed 20 MVA patients who underwent either surgical interventions or conservative follow-ups at the Zhongnan Hospital of Wuhan University between 2017 and 2021. We examined their clinical, echocardiographic, and surgical records and tracked their long-term outcomes.Results: Of the 20 patients, 12 were diagnosed with MVA using transthoracic echocardiography, seven required additional transesophageal echocardiography for a more definitive diagnosis, and one child was diagnosed during surgery. In all these patients, the MVAs were detected in the anterior mitral leaflet. We found that 15 patients (75%) were associated with infective endocarditis (IE), whereas the remaining patients were associated with bicuspid aortic valve and moderate aortic regurgitation (AR) and mild aortic stenosis (5%), congenital heart disease (5%), elderly calcified valvular disease (5%), mitral valve prolapse (5%), and unknown reasons (5%). Of the 17 patients who underwent hospital surgical interventions, two died due to severe cardiac events. The remaining 15 patients had successful surgeries and were followed up for an average of 13.0 ± 1.8 months. We observed an improvement in their New York Heart Association functional class and mitral regurgitation and AR degrees (P-value < 0.001). During follow-up, only one infant had an increased left ventricular end-diastolic diameter and left ventricular end-systolic diameter, whereas the remaining 14 patients had decreased values (P < 0.001). In addition, none of the three conservatively managed patients experienced disease progression during the 7–24 months of follow-up.Conclusions: We recommend using echocardiography as a highly sensitive method for MVA diagnosis. Although most cases are associated with IE or AR, certain cases still require further study to determine their causes. A prompt diagnosis of MVA in patients using echocardiography can aid in its timely management.

Introduction: Severe respiratory illness is the most prominent manifestation of patients infected with SARS-CoV-2, and yet the molecular mechanisms underlying severe lung disease in COVID-19 affected patients still require elucidation. Human leukocyte antigen class I (HLA-I) expression is crucial for antigen presentation and the host’s response to SARS-CoV-2.Methods: To gain insights into the immune response and molecular pathways involved in severe lung disease, we performed immunopeptidomic and proteomic analyses of lung tissues recovered at four COVID-19 autopsy and six non-COVID-19 transplants.Results: We found signals of tissue injury and regeneration in lung fibroblast and alveolar type I/II cells, resulting in the production of highly immunogenic self-antigens within the lungs of COVID-19 patients. We also identified immune activation of the M2c macrophage as the primary source of HLA-I presentation and immunogenicity in this context. Additionally, we identified 28 lung signatures that can serve as early plasma markers for predicting infection and severe COVID-19 disease. These protein signatures were predominantly expressed in macrophages and epithelial cells and were associated with complement and coagulation cascades.Discussion: Our findings emphasize the significant role of macrophage-mediated immunity in the development of severe lung disease in COVID-19 patients.

The importance of the stromal microenvironment in chronic lymphocytic leukemia (CLL) pathogenesis and drug resistance is well established. Despite recent advances in CLL therapy, identifying novel ways to disrupt interactions between CLL and its microenvironment may identify new combination partners for the drugs currently in use. To understand the role of microenvironmental factors on primary CLL cells, we took advantage of an observation that conditioned media (CM) collected from stroma was protective of CLL cells from spontaneous cell death ex vivo. The cytokine in the CM-dependent cells that most supports CLL survival in short-term ex vivo culture was CCL2. Pretreatment of CLL cells with anti-CCL2 antibody enhanced venetoclax-mediated killing. Surprisingly, we found a group of CLL samples (9/23 cases) that are less likely to undergo cell death in the absence of CM support. Functional studies revealed that CM-independent (CMI) CLL cells are less sensitive to apoptosis than conventional stroma-dependent CLL. In addition, a majority of the CMI CLL samples (80%) harbored unmutated immunoglobulin heavy-chain variable (IGHV) region. Bulk-RNA sequence analysis revealed upregulation of the focal adhesion and RAS signaling pathways in this group, along with expression of fms-like tyrosine kinase 3 (FLT3) and CD135. Treatment with FLT3 inhibitors caused a significant reduction in cell viability among CMI samples. In summary, we were able to discriminate and target 2 biologically distinct subgroups of CLL based on CM dependence with distinct microenvironmental vulnerabilities.