RAS mutations, present in 40-50% of metastatic colorectal cancer (mCRC) cases, drive oncogenic signaling and confer resistance to anti-EGFR therapies. Tumor mutational burden (TMB), a marker of genomic instability, has recently emerged as a predictive biomarker of response to immunotherapy. However, the prognostic interaction between RAS status and TMB in mCRC remains poorly defined.

Neoadjuvant chemoimmunotherapy does not benefit all non-small cell lung cancer (NSCLC) patients, and reliable biomarkers are urgently needed. We conducted this prospective phase II trial of neoadjuvant chemoimmunotherapy to explore the role of cell-free DNA (cfDNA) features in pathological response assessment.

Cancer-associated fibroblasts (CAFs) are key regulators of the tumor microenvironment, yet their spatial organization and immunomodulatory functions in H. pylori-associated gastric cancer (GC) remain incompletely understood.

Cervical cancer remains a major threat to women's health worldwide. Discoidin domain receptor 1 (DDR1) drives immune evasion in a variety of cancers, but its expression pattern, clinical significance, and immunoregulatory mechanisms in cervical cancer have not been clarified.

Single nucleotide variants are important factors involved in lung cancer onset and prognosis. In Cuba, there are scarce studies evaluating the possible association between genetic variants and lung cancer. Here, we described the frequency distribution of genetic variants in DNA repair related genes and assessed their impact on lung cancer susceptibility and survival prognosis in a cohort of Cuban population METHODS: Case-Control study included 300 lung cancer patients and 300 control subjects. Variants: rs1042522, rs11016879, rs13181, rs25487 and rs861539 were genotyped. The association analysis was evaluated by logistic regression and the impact on overall survival was estimated by Kaplan-Meier and Cox regression analyses.

CircRNAs have a potential regulatory effect on Renal cell carcinoma (RCC). However, there is still a significant lack of research on their action pathways and mechanisms in the treatment of RCC. The aim of this study is to identify the effects of Circ_001024 on the proliferation, migration, and invasion of RCC cells, and to elucidate the molecular mechanisms by which Circ_001024 promotes the malignant biological behaviors of RCC cell lines.

NETO2 is a gene with potential prognostic value in various cancers, but its role in oral squamous cell carcinoma (OSCC) remains unclear. This study investigates NETO2 expression, clinical significance, and its association with the tumor immune microenvironment in OSCC.

Multiple Myeloma (MM) is a hematological malignancy originating from the bone marrow and affecting the germinal lymphoid B cells, resulting in abnormal plasma cells and end organ damage. Genetic profiling is necessary for risk stratification and optimized management. The genetics of MM patients in the Middle East, particularly in Lebanon, have been scarcely reported. This lack of data can adversely affect the decision-making process and the establishment of guidelines and standardized protocols.

Breast cancer (BRCA) is a complex cancer with heterogeneous molecular mechanisms. This study aimed to identify prognostic genes related to T cell exhaustion and mitochondrial dysfunction in BRCA, and to construct a prognostic model. First, transcriptomic and clinical data for both tumor and normal samples were retrieved from public databases. Next, differentially expressed genes (DEGs) were identified. These DEGs were then intersected with 2030 mitochondrial-related genes and 683 T cell exhaustion-related genes obtained from relevant databases to pinpoint candidate genes. Moreover, regression analyses were carried out to refine the prognostic genes. A risk model was established to assess the risk score of BRCA patients. Cox regression analyses were utilized to determine the independent prognostic factors. Then a prognostic model was constructed. In addition, immune infiltration, drug sensitivity, and single-cell transcriptomics were integrated to dissect mechanisms. The expression of these genes in BRCA was validated by quantitative reverse transcription polymerase chain reaction (RT-qPCR). From 5041 DEGs, regression identified 7 prognostic genes (BCL2A1, GZMB, IRF7, MTHFD2, TFRC, JUN, and PPP1R15A). The accurate risk model stratified patients: high-risk correlated with suppressed immunity (p < 2.2e-16), elevated TIDE (p = 5.4e-14), and higher CI.1040 IC50 (cor = 0.63, p < 0.0001). Single-cell analysis revealed 6 types and MIF-(CD74 + CD44) crosstalk. RT-qPCR confirmed MTHFD2, TFRC, IRF7, BCL2A1 upregulation in tumor (p < 0.05). Risk score, age, race, N/M-stage were independent factors. Seven prognostic genes effectively predicted BRCA prognosis with independent prognostic factors.

Immunotherapy has revolutionized hematologic cancer treatment, yet responses remain unpredictable due to primary resistance, relapse, and life-threatening toxicities. Conventional biomarkers fail to capture the complexity of tumor-immune interactions, necessitating integrative approaches. This review explores how multi-omics technologies, genomics, transcriptomics, proteomics, metabolomics, spatial omics, and microbiome profiling, decode the molecular drivers of immunotherapy efficacy and adverse events in hematologic malignancies. We highlight key advances: genomics reveals neoantigen landscapes and HLA diversity shaping checkpoint inhibitor responses; transcriptomics identifies T-cell exhaustion signatures predictive of CAR-T failure; metabolomics uncovers lactate-driven immunosuppression in AML; and spatial omics maps immune architectures linked to Hodgkin lymphoma outcomes. Supervised machine learning algorithms (e.g., random forest, support vector machines) integrate these layers to build predictive models for cytokine release syndrome (CRS) and resistance, while longitudinal ctDNA monitoring enables dynamic therapy adaptation. Emerging frontiers like CRISPR-based epitope editing, digital twins for in silico clinical trials, and non-coding RNA biomarkers further refine precision strategies. Despite challenges in data integration, tumor plasticity, and ethical frameworks, multi-omics is accelerating biomarker-driven trial designs (e.g., basket trials with omics stratification) and patient-centric tools (wearable sensors for real-time metabolite tracking). This review distinguishes itself by synthesizing these rapid technological advances not only to predict outcomes but also to chart a forward-looking roadmap for their clinical translation, offering a unique perspective on overcoming the current barriers to precision immuno-oncology. Together, these advances promise to transform immunotherapy from empirical to precision medicine, optimizing outcomes for leukemia, lymphoma, and myeloma patients.

Myasthenia gravis (MG) is an autoimmune disorder mediated by B-cells, characterized by muscle weakness and fatigue. Mitochondria, essential for energy production and muscle function, have been implicated in MG. Despite their importance, the exact relationship between mitochondrial proteins (MPs) and MG remains unclear. This study utilized two-sample Mendelian Randomization (TSMR) to investigate potential causal associations between MPs and MG. Data from the largest available genome-wide associated study (GWAS), comprising 1873 acetylcholine receptor (AchR) antibody-positive MG patients (1278 late-onset MG [LOMG] and 595 early-onset MG [EOMG]), were analyzed. A total of 66 MPs were selected as exposure variables, with MG and its subtypes as outcomes. Analyses employed inverse variance weighted (IVW), MR-PRESSO, MR-Egger, and weighted median methods, with heterogeneity assessed using Cochran's Q statistic. Significant causal associations were found between MPs and MG subtypes. For LOMG, GrpE protein homolog 1, oligoribonuclease, protein SCO1 homolog, and rRNA methyltransferase 3 were linked to increased risk. Cytochrome c oxidase subunit 7A1 was associated with higher EOMG risk, while [pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 1, dihydrolipoyl dehydrogenase, and NFU1 iron-sulfur cluster scaffold were linked to reduced EOMG risk. MPs such as dihydrolipoyl dehydrogenase and NAD-dependent protein deacylase sirtuin-5 showed protective effects against MG, while GrpE protein homolog 1, mitochondrial glutamate carrier 2, oligoribonuclease, and protein SCO1 homolog were associated with increased risk. This MR analysis suggests potential causal relationships between MPs and MG, highlighting the need for further research to validate these findings and explore the mechanisms underlying these associations.

This study evaluated the diagnostic value of clinicopathological features and immunohistochemical markers for distinguishing lipomas from atypical lipomatous tumors/well-differentiated liposarcomas (ALT/WDLPS). An integrated diagnostic model for ALT/WDLPS was developed to guide diagnosis, treatment planning, and prognosis. This retrospective analysis included 216 patients with lipomatous tumors diagnosed between February 2018 and December 2024, including lipomas (n = 149), spindle cell lipomas (n = 3), ALTs/WDLPs (n = 62), and WDLPS with a low-grade de-differentiated component (n = 2). Immunohistochemical data for MDM2, CDK4, and p16 were available for 131 patients. MDM2 amplification was significantly more frequent in patients ≥ 55 years and in tumors of the lower limbs (the thigh) and retroperitoneum (p = 0.000). Larger tumor size and multiplicity were also associated with MDM2 amplification (p < 0.05). Immunohistochemistry sensitivities for ALT/WDLPS vs. lipomas: 65% (MDM2), 100% (CDK4), and 80.4% (p16); combined, the specificity was 100% and sensitivity 85.6%. The diagnostic model achieved 93.3% sensitivity and 72.2% specificity. Scores < 0.219 indicated a higher likelihood of lipoma, while scores > 0.652 indicated a higher likelihood of liposarcoma. Age ≥ 55 years, lower extremity/retroperitoneal location, tumor diameter ≥ 9.9 cm, and positive markers were independent risk factors. This model provides an effective tool for ALT/WDLPS identification.

Post-transcriptional diversification of RNA transcripts mediated by complex processing machinery, including DEAD-box ATPases, establishes and maintains cellular phenotypes. For example, DDX41 controls RNA splicing, innate immune signaling, and genome stability. Although heterozygous DDX41 germline genetic variation occurs in familial myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), the DDX41 contributions to splicing globally, biological processes, and pathogenic mechanisms are incompletely defined. Using a genetic rescue system with Ddx41+/- myeloid progenitors, we established global wildtype DDX41 and pathogenic variant mechanisms. Differing from pathogenic variants of other RNA splicing regulators, DDX41 deficiency compromised multiple splicing steps. DDX41-regulated transcripts encoded factors controlling RNA splicing, including Cdc2-like kinase 3 (CLK3). DDX41 regulated Clk3 transcripts, and elevated CLK3 during myeloid differentiation. Loss-of-function analysis revealed DDX41-regulated splicing commonly, but not always, required CLK3. Thus, through a mechanism utilizing a splicing factor kinase that itself is DDX41-regulated, DDX41 establishes transcript ensembles in myeloid progenitors.

Circular single-stranded DNA (cssDNA), an emerging nucleic acid vector, exhibits significant clinical potential for treating genetic disorders, enabling gene editing, and advancing oncotherapy. Its unique attributes, including high stability, structural simplicity, conformational flexibility, and low molecular mass, establish it as a promising gene therapy tool. Our study reveals that cssDNA demonstrates superior expression efficiency over conventional plasmids across diverse tumor cell lines. Notably, cssDNA expression is enhanced under certain tumor microenvironment (TME) conditions (glucose deficiency, glutamine deficiency and hypoxia) compared to normal condition. Mechanistically, these TME conditions induce significant cell cycle perturbations, particularly pronounced G1 arrest. Intriguingly, transfected cssDNA expression peaks during the late G2/M phase, immediately preceding entry into the G1 phase. We further identify S-phase kinase-associated protein 2 (SKP2) as a critical regulator of cssDNA expression under TME conditions. SKP2 inhibition directly or indirectly notably enhances the expression levels of cssDNA. These findings confirm cssDNA's advantages as a gene expression vector and how specific TME conditions modulate its expression via cell cycle and SKP2-dependent mechanisms in vitro. This work provides a scientific foundation for cssDNA-based cancer therapy and opens new avenues for future clinical translation.

Transmembrane protein 166 (TMEM166), an endoplasmic reticulum (ER)-resident membrane protein, exerts anticancer effects by inducing autophagy and apoptosis. Although tissues of various cancers downregulate its expression, the biological function of TMEM166 in hepatocellular carcinoma (HCC) remains unclear. Herein, we report that TMEM166 negatively regulates unfolded protein response (UPR) in HCC. TMEM166 was noted to interact with ACSL3 to maintain ACSL3 stability and facilitate lipid storage. TMEM166 deletion reduced ACSL3 expression and increased lipid utilisation in the mitochondria through fatty acid β-oxidation (FAO), ultimately boosting ATP production. Moreover, TMEM166-knockout (KO) cells demonstrated accelerated protein synthesis via the AMPK-mTOR axis. These effects induced sublethal ER stress and UPR activation in TMEM166-KO cells. Furthermore, TMEM166 KO promoted HCC cell proliferation and sorafenib resistance via UPR activity upregulation. We analysed the clinical significance of TMEM166-regulated UPR in human HCC cells and noted that TMEM166 expression was negatively correlated with the activities of UPR-related transcriptional factors such as ATF4, ATF6 and XBP1s in the cells. This study is the first to elucidate the relationship among TMEM166, ER stress, and HCC and may provide and indicate newer avenues for TMEM166-targeted gene therapy strategies for HCC treatment.

Mantle cell lymphoma (MCL) is a genetically and clinically heterogeneous B-cell malignancy. We studied two MCL cohorts with differing treatment patterns: one enriched for immunochemotherapy, the other for chemotherapy alone. TP53 alterations are consistently associated with poor prognosis, whereas ATM mutations correlate with improved outcomes following rituximab-based chemotherapy. Based on recurrent genetic events, six clusters are identified and refined into three prognostic groups: high-risk (TP53 mutations and deletions at 17p13.3, 13q14.2, and 19p13.3), intermediate-risk (ATM and epigenetic regulator mutations, or gains at 8q/17q/15q), and low-risk (lacking TP53 alterations, rare ATM mutations without 11q deletions, gains at 3q, deletions at 6q). Transcriptomic analysis reveals enrichment of proliferation, metabolism-promoting gene signatures in high-risk; angiogenesis and NOTCH signaling in intermediate-risk; and proinflammatory-related (i.e., IFNα, TNFα) in low-risk MCLs. Multi-proteomic spatial profiling using imaging mass cytometry (IMC) demonstrates enrichment of CD4⁺ T cells with high expression of exhaustion markers and a dominant population of myeloid cells skewed toward an M2-like phenotype. Spatially, TP53-perturbed MCLs are immune-infiltrated yet exhausted, while ATM-perturbed cases remain immune-cold with dense tumors. Functional analysis shows that p53 represses BCR signaling through PTPN6 activation. Collectively, these findings highlight distinct molecular and immune landscapes and reveal therapeutic vulnerabilities in high-risk TP53-perturbed MCL.

Mastocytosis, a clonal disorder characterized by the accumulation of mast cells in various tissues, affects both adults and children. Adults frequently exhibit KIT activating mutations, usually in the phospho-transferase domain (PTD KIT mutations). Our previous findings revealed that children also harbor oncogenic KIT activating mutations, but more commonly within the extra-cellular domain (non-PTD KIT mutations). While the disease persists chronically in adults, it often regresses spontaneously in children through an unknown mechanism. Here, we report that tumor senescence in childhood mastocytosis may be triggered by significantly shortened telomeres in mast cells harboring non-PTD KIT mutations compared to those with PTD KIT mutations. In vitro models further demonstrated a senescent phenotype associated with shorter telomeres for the non-PTD KIT mutant compared to the PTD KIT mutant. Mechanistically, we found that telomere shortening in mast cells from children with non-PTD KIT mutations is linked with increased p38 MAP-kinase activation, resulting in lower TRF2 occupancy on telomeres. Thus, non-PTD KIT mutations trigger distinct signaling pathways leading to telomere shortening and cellular senescence, providing mechanistic insights into the differing outcomes between childhood- and adult-onset mastocytosis.

Imatinib is associated with significant toxicities, including myelosuppression, oedema, and hypersensitivity, with considerable interpatient variability. Pharmacokinetic and pharmacogenomic factors contribute, but comprehensive biomarkers are yet to be identified. A retrospective cohort study was conducted on 154 gastrointestinal stromal tumour (GIST) patients receiving imatinib. Steady-state concentrations of imatinib and its metabolite were measured using liquid chromatography-tandem mass spectrometry. Thirty-five genetic polymorphisms in signaling, transporter, and immune genes were genotyped, and multivariate logistic regression was performed, adjusting for clinical covariates. The study found a significant correlation between myelosuppression and imatinib plasma concentration, along with genetic polymorphisms in FLT1, MAPK1, PDGFRB, and SHC1. Peripheral oedema was more prevalent in females and associated with PDGFRB polymorphisms. Hypersensitivity was linked to EGFR and CXCL14 polymorphisms. These findings identify novel pharmacogenetic markers for imatinib-induced toxicities, supporting the potential of personalized treatment strategies through genetic testing and therapeutic drug monitoring. Further validation in larger cohorts is needed.

Head and neck squamous cell carcinoma (HNSCC) remains a prevalent and aggressive malignancy, characterized by a lack of targeted therapies and limited clinical benefits. Here, we conducted an optimized whole-genome CRISPR screen across five HNSCC cell lines aimed at identifying actionable genetic vulnerabilities for rapid preclinical evaluation as novel targeted therapies. Given their critical role in cancer, cyclin-dependent kinases (CDKs) were prioritized for further investigation. Among these, CDK7 was identified as an essential and targetable gene across all five cell lines, prompting its selection for in-depth functional and molecular characterization. Genetic and pharmacological inhibition of CDK7 significantly and consistently reduced tumor cell proliferation due to generalized cell cycle arrest and apoptosis induction. Additionally, CDK7 knockout (KO) and selective inhibitors (YKL-5-124 and samuraciclib) demonstrated potent antitumor activity, effectively suppressing tumor growth in HNSCC patient-derived organoids (PDOs), as well as in both cell line- and patient-derived xenograft (PDX) mouse models with minimal toxicity. Mechanistically, CDK7 inhibition led to a broad downregulation of gene sets related to cell cycle progression and DNA repair, and significantly reduced the transcription of essential genes and untargetable vulnerabilities identified by our CRISPR screen. These findings highlight CDK7 as a promising therapeutic target for HNSCC. Our study provides strong evidence of the robust antitumor activity of CDK7-selective inhibition in disease-relevant preclinical models, strongly supporting its progression to clinical testing.

HERPUD1 is a protein of the endoplasmic reticulum (ER) that is sensitive to the unfolded protein response (UPR) induced during ER stress and has been linked to ER stress tolerance in cancer cells. Many tumors, including triple-negative breast cancer (TNBC), which lacks an effective treatment, display UPR activity as a malignancy trait. However, whether HERPUD1 provides an ER-dependent mechanistic link for tumorigenic agents and/or potential therapeutic targets remains unknown. To address these possibilities, we first analyzed HERPUD1 expression in breast cancer (BC) biopsies via immunohistochemistry and immunofluorescence, revealing significantly higher levels in BC, including luminal A and TNBC, compared to non-malignant tissue. In TNBC, in addition to epithelial cells, HERPUD1 associated with inflammatory infiltrates, highlighting its potential role in tumor progression. Palmitic acid (PA), a dietary saturated fatty acid, is an obesity-associated tumor risk factor that induces ER stress and activates UPR. Interestingly, MDA-MB-231 cells, but not other BC cell lines, specifically upregulate HERPUD1 together with XBP1s and ATF4, key UPR factors, in response to PA, whereas TG treatment elevated HERPUD1 across all tested cell lines. HERPUD1 silencing reduced TNBC cell proliferation, migration, and invasion while enhancing doxorubicin (DOX) cytotoxicity, in both 2D and 3D cell culture models. HERPUD1 ablation also elevated UPR activation under TG. In contrast, PA-induced stress led to reduced UPR activation and lower IL-6 and IL-8 levels in the absence of HERPUD1 expression. We identified CK2 as a kinase that regulates HERPUD1 stability via Ser-59 phosphorylation. Strikingly, inhibition of CK2 with CX-4945 not only reduced HERPUD1 levels but also increased the sensitivity of BC cells to DOX. HERPUD1-S59D phosphomimetic mutants showed opposite effects.Our findings establish HERPUD1 as a key mediator of PA-driven aggressiveness, dependent on the lipid-handling capacity of TNBC cells and reveals a mechanistic to lipid stress and tumor progression.