Epigenetic regulation of major histocompatibility complexes in gastrointestinal malignancies and the potential for clinical interception.

BACKGROUND: Gastrointestinal malignancies encompass a diverse group of cancers that pose significant challenges to global health. The major histocompatibility complex (MHC) plays a pivotal role in immune surveillance, orchestrating the recognition and elimination of tumor cells by the immune system. However, the intricate regulation of MHC gene expression is susceptible to dynamic epigenetic modification, which can influence functionality and pathological outcomes. MAIN BODY: By understanding the epigenetic alterations that drive MHC downregulation, insights are gained into the molecular mechanisms underlying immune escape, tumor progression, and immunotherapy resistance. This systematic review examines the current literature on epigenetic mechanisms that contribute to MHC deregulation in esophageal, gastric, pancreatic, hepatic and colorectal malignancies. Potential clinical implications are discussed of targeting aberrant epigenetic modifications to restore MHC expression and 0 the effectiveness of immunotherapeutic interventions. CONCLUSION: The integration of epigenetic-targeted therapies with immunotherapies holds great potential for improving clinical outcomes in patients with gastrointestinal malignancies and represents a compelling avenue for future research and therapeutic development.

Hypoxia-responsive lncRNA MIR155HG promotes PD-L1 expression in hepatocellular carcinoma cells by enhancing HIF-1α mRNA stability.

The microenvironment of hepatocellular carcinoma (HCC) is characterized by hypoxia, which leads to immune evasion of HCC. Therefore, gaining a comprehensive understanding of the mechanism underlying the impact of hypoxia on HCC cells may provide valuable insights into immune checkpoint therapy. Based on analysis of databases and clinical samples, we observed that expression level of programmed cell death ligand 1 (PD-L1) and long non-coding RNA (lncRNA) MIR155HG in patients in the hypoxia group were higher than those in the non-hypoxia group. Furthermore, there was a positive correlation between the expression of PD-L1 and MIR155HG with that of HIF-1α. In vitro experiments using hypoxic treatment demonstrated an increase in PD-L1 and MIR155HG expression levels in HCC cells. While the hypoxia-induced upregulation of PD-L1 could be reversed by knocking down MIR155HG. Mechanistically, as a transcription factor, HIF-1α binds to the promoter region of MIR155HG to enhance its transcriptional activity under hypoxic conditions. Hypoxia acts as a stressor promoting nuclear output of ILF3 leading to increased binding of ILF3 to MIR155HG, thereby enhancing stability for HIF-1α mRNA. In vivo, knocking down MIR155HG inhibit subcutaneous tumor growth, reduce the expression of HIF-1α and PD-L1 within tumors; additionally, it enhances anti-tumor immunity response. These findings suggested that through inducing MIR155HG to interact with ILF3, hypoxia increases HIF-1α mRNA stability resulting in elevated PD-L1 expression in HCC and thus promoting immune escape. In summary, this study provides new insights into the effects of hypoxia on HCC immunosuppression.

Immune evasion impacts the landscape of driver genes during cancer evolution.

BACKGROUND: Carcinogenesis is driven by interactions between genetic mutations and the local tumor microenvironment. Recent research has identified hundreds of cancer driver genes; however, these studies often include a mixture of different molecular subtypes and ecological niches and ignore the impact of the immune system. RESULTS: In this study, we compare the landscape of driver genes in tumors that escaped the immune system (escape +) versus those that did not (escape -). We analyze 9896 primary tumors from The Cancer Genome Atlas using the ratio of non-synonymous to synonymous mutations (dN/dS) and find 85 driver genes, including 27 and 16 novel genes, in escape - and escape + tumors, respectively. The dN/dS of driver genes in immune escaped tumors is significantly lower and closer to neutrality than in non-escaped tumors, suggesting selection buffering in driver genes fueled by immune escape. Additionally, we find that immune evasion leads to more mutated sites, a diverse array of mutational signatures and is linked to tumor prognosis. CONCLUSIONS: Our findings highlight the need for improved patient stratification to identify new therapeutic targets for cancer treatment.

PRMT6 Promotes the Immune Evasion of Gastric Cancer by Upregulating ANXA1.

Gastric cancer is a most malignancy in digestive tract worldwide. This study aimed to investigate the roles of protein arginine methyltransferase 6 (PRMT6) in gastric cancer. Immunohistochemistry was performed to detect PRMT6 expression in gastric tumors. Real-time transcriptase-quantitative polymerase chain reaction (RT-qPCR) was used to detected mRNA levels. Protein expression was determined using western blot. Gastric cancer cells were co-cultured with CD8+ T cells. Colony formation assay was performed to detect cell proliferation. Flow cytometry was performed to determine CD8+ T cell function and tumor cell apoptosis. PRMT6 was overexpressed in gastric tumors. High level of PRMT6 predicted poor outcomes of gastric cancer patients and inhibition of CD8+ T cell infiltration. PRMT6 promoted proliferation of CD8+ T cells and enhanced its tumor killing ability. Moreover, PRMT6 upregulated annexin A1 (ANXA1) and promoted ANXA1 protein stability. ANXA1 overexpression suppressed the proliferation of CD8+ T cells and promoted tumor cell survival. PRMT6 functions as an oncogene in gastric cancer. PRMT6-mediated protein stability inhibits the infiltration of CD8+ T cells, resulting in immune evasion of gastric cancer. The PRMT6-ANXA1 may be a promising strategy for gastric cancer.

Exploring the immune escape mechanisms in gastric cancer patients based on the deep AI algorithms and single-cell sequencing analysis.

Gastric cancer is a prevalent and deadly malignancy, and the response to immunotherapy varies among patients. This study aimed to develop a prognostic model for gastric cancer patients and investigate immune escape mechanisms using deep machine learning and single-cell sequencing analysis. Data from public databases were analysed, and a prediction model was constructed using 101 algorithms. The high-AIDPS group, characterized by increased AIDPS expression, exhibited worse survival, genomic variations and immune cell infiltration. These patients also showed immunotherapy tolerance. Treatment strategies targeting the high-AIDPS group identified three potential drugs. Additionally, distinct cluster groups and upregulated AIDPS-associated genes were observed in gastric adenocarcinoma cell lines. Inhibition of GHRL expression suppressed cancer cell activity, inhibited M2 polarization in macrophages and reduced invasiveness. Overall, AIDPS plays a critical role in gastric cancer prognosis, genomic variations, immune cell infiltration and immunotherapy response, and targeting GHRL expression holds promise for personalized treatment. These findings contribute to improved clinical management in gastric cancer.

Downregulation of lncRNA MIR17HG reduced tumorigenicity and Treg-mediated immune escape of non-small-cell lung cancer cells through targeting the miR-17-5p/RUNX3 axis.

Long noncoding RNA MIR17HG was involved with the progression of non-small-cell lung cancer (NSCLC), but specific mechanisms of MIR17HG-mediated immune escape of NSCLC cells were still unknown. The present study investigated the function of MIR17HG on regulatory T cell (Treg)-mediated immune escape and the underlying mechanisms in NSCLC. Expression of MIR17HG and miR-17-5p in NSCLC tissue samples were detected using quantitative real-time PCR (qRT-PCR). A549 and H1299 cells were transfected with sh-MIR17HG, miR-17-5p inhibitor, or sh-MIR17HG + miR-17-5p inhibitor, followed by cocultured with Tregs. Cell proliferation was measured using 5-ethynyl-20-deoxyuridine (Edu) staining assay and cell counting kit-8 (CCK-8) assay. Flow cytometry was used for determining positive numbers of FOXP3+CD4+/CD25+/CD8+ Tregs. Through subcutaneous injection with transfected A549 cells, a xenograft nude mouse model was established. Weights and volumes of xenograft tumors were evaluated. Additionally, the expressions of immune-related factors including transforming growth factor beta (TGF-ß), vascular endothelial growth factor A (VEGF-A), interleukin-10 (IL-10), IL-4, and interferon-gamma (IFN-γ) in cultured cells, were evaluated by enzyme-linked immunosorbent assay and western blot analysis. Then, miR-17-5p was decreased and MIR17HG was enhanced in both NSCLC tissues and cell lines. MIR17HG knockdown significantly suppressed cell proliferation, tumorigenicity, and immune capacity of Tregs in A549 and H1299 cells, whereas sh-MIR17HG significantly reduced expression levels of VEGF-A, TGF-ß, IL-4, and IL-10 but promoted the IFN-γ level in vitro and in vivo. Moreover, downregulation of miR-17-5p significantly reversed the effects of sh-MIR17HG. Additionally, we identified that runt- related transcription factor 3 (RUNX3) was a target of miR-17-5p, and sh-MIR17HG and miR-17-5p mimics downregulated RUNX3 expression. In conclusion, downregulation of MIR17HG suppresses tumorigenicity and Treg-mediated immune escape in NSCLC through downregulating the miR-17-5p/RUNX3 axis, indicating that this axis contains potential biomarkers for NSCLC.

Unveiling the role of the KLF4/Lnc18q22.2/ULBP3 axis in the tumorigenesis and immune escape of hepatocellular carcinoma under hypoxic condition.

Hepatocellular carcinoma (HCC) represents a significant global health burden, necessitating an in-depth exploration of its molecular underpinnings to facilitate the development of effective therapeutic strategies. This investigation delves into the complex role of long non-coding RNAs (lncRNAs) in the modulation of hypoxia-induced HCC progression, with a specific emphasis on delineating and functionally characterizing the novel KLF4/Lnc18q22.2/ULBP3 axis. To elucidate the effects of hypoxic conditions on HCC cells, we established in vitro models under both normoxic and hypoxic environments, followed by lncRNA microarray analyses. Among the lncRNAs identified, Lnc18q22.2 was found to be significantly upregulated in HCC cells subjected to hypoxia. Subsequent investigations affirmed the oncogenic role of Lnc18q22.2, highlighting its critical function in augmenting HCC cell proliferation and migration. Further examination disclosed that Kruppel-like factor 4 (KLF4) transcriptionally governs Lnc18q22.2 expression in HCC cells, particularly under hypoxic stress. KLF4 subsequently enhances the tumorigenic capabilities of HCC cells through the modulation of Lnc18q22.2 expression. Advancing downstream in the molecular cascade, our study elucidates a novel interaction between Lnc18q22.2 and UL16-binding protein 3 (ULBP3), culminating in the stabilization of ULBP3 protein expression. Notably, ULBP3 was identified as a pivotal element, exerting dual functions by facilitating HCC tumorigenesis and mitigating immune evasion in hypoxia-exposed HCC cells. The comprehensive insights gained from our research delineate a hitherto unidentified KLF4/Lnc18q22.2/ULBP3 axis integral to the understanding of HCC tumorigenesis and immune escape under hypoxic conditions. This newly unveiled molecular pathway not only enriches our understanding of hypoxia-induced HCC progression but also presents novel avenues for therapeutic intervention.

Determinants of gastric cancer immune escape identified from non-coding immune-landscape quantitative trait loci.

The landscape of non-coding mutations in cancer progression and immune evasion is largely unexplored. Here, we identify transcrptome-wide somatic and germline 3' untranslated region (3'-UTR) variants from 375 gastric cancer patients from The Cancer Genome Atlas. By performing gene expression quantitative trait loci (eQTL) and immune landscape QTL (ilQTL) analysis, we discover 3'-UTR variants with cis effects on expression and immune landscape phenotypes, such as immune cell infiltration and T cell receptor diversity. Using a massively parallel reporter assay, we distinguish between causal and correlative effects of 3'-UTR eQTLs in immune-related genes. Our approach identifies numerous 3'-UTR eQTLs and ilQTLs, providing a unique resource for the identification of immunotherapeutic targets and biomarkers. A prioritized ilQTL variant signature predicts response to immunotherapy better than standard-of-care PD-L1 expression in independent patient cohorts, showcasing the untapped potential of non-coding mutations in cancer.

Inherited KDM6AA649T facilitates tumor-immune escape and exacerbates colorectal signet-ring cell carcinoma outcomes.

Childhood onset of colorectal signet-ring cell carcinoma (CR-SRCC) is extremely rare and featured as highly malignant with poor prognosis. Here we reported a CR-SRCC case of 11-year-old boy with a novel inherited X-linked KDM6AA694T mutation. The H3K27me3 demethylase KDM6A was frequently mutated in varieties of tumors and acts as a tumor suppressor. In vivo H3K27me3 demethylation assay demonstrated that KDM6AA694T had dampened H3K27me3 demethylase activity. Overexpression of KDM6AA694T in SRCC cell line KATO3 promoted cell proliferation, invasion and migration, which were further confirmed in vivo by constructing orthotopic tumor growth and lung metastasis model. Besides, expression of KDM6AA694T in immune cells suppresses inflammatory macrophage response and effector T cell response. In conclusion, we characterized a novel inherited KDM6AA694T mutant from a childhood-onset SRCC case and demonstrated that the mutant with impaired H3K27me3 demethylase activity could potentiate tumor malignancy and suppress antitumor immunity.

FOXA1/UBE2T Inhibits CD8+T Cell Activity by Inducing Mediates Glycolysis in Lung Adenocarcinoma.

BACKGROUND: Immune escape is a key factor influencing survival rate of lung adenocarcinoma (LUAD) patients, but molecular mechanism of ubiquitin binding enzyme E2T (UBE2T) affecting immune escape of LUAD remains unclear. The objective was to probe role of UBE2T in LUAD. METHODS: Bioinformatics means were adopted for analyzing UBE2T and forkhead box A1 (FOXA1) expression in LUAD tissues, the gene binding sites, the pathway UBE2T regulates, and the correlation between UBE2T and glycolysis genes. Dual luciferase and chromatin immunoprecipitation (ChIP) assays were conducted for validating the binding relationship between the two genes. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot were employed to evaluate UBE2T, FOXA1, and programmed death ligand 1 (PD-L1) levels in cancer cells. MTT assay was conducted for detecting cell viability. Cytotoxicity assay detected CD8+T cell toxicity. Cytokine expression was assayed by enzyme linked immunosorbent assay (ELISA). Extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) were assayed by extracellular flow analyzer. Glycolytic gene expression was analyzed by qRT-PCR, and glycolysis-related indicators were detected by ELISA. Immunohistochemistry (IHC) detected CD8+T cell infiltration in tumor tissues. RESULTS: FOXA1 and UBE2T were up-regulated in LUAD, and a binding site existed between UBE2T and FOXA1. Overexpressing UBE2T could increase PD-L1 expression and inhibit toxicity of CD8+T cells to LUAD cells. Overexpressing UBE2T repressed CD8+T cell activity in LUAD by activating the glycolysis pathway, and the addition of glycolysis inhibitor 2-deoxy-d-glucose (2-DG) reversed the above results. Mechanistically, FOXA1 promoted the immune escape of LUAD by up-regulating UBE2T and thus mediating glycolysis. In vivo experiments revealed that UBE2T knockdown hindered tumor growth, inhibited PD-L1 expression, and facilitated CD8+T cell infiltration. CONCLUSION: FOXA1 up-regulated the expression of UBE2T, which activated glycolysis, and thus inhibited activity of CD8+T cells, causing immune escape of LUAD.

Multi-omics comprehensive analysis reveals the predictive value of N6-methyladenosine- related genes in prognosis and immune escape of bladder cancer.

BACKGROUND: N6-methyladenosine (m6A) is the most frequent RNA modification in mammals, and its role in bladder cancer (BC) remains rarely revealed. OBJECTIVE: To predict the value of m6A-related genes in prognosis and immunity in BC. METHODS: We performed multiple omics analysis of 618 TCGA and GEO patients and used principal component analysis (PCA) to calculate the m6A score for BC patients. RESULTS: We described the multiple omics status of 23 m6A methylation-related genes (MRGs), and four m6A clusters were identified, which showed significant differences in immune infiltration and biological pathways. Next, we intersected the differential genes among m6A clusters, and 11 survival-related genes were identified, which were used to calculate the m6A score for the patients. We found that the high-score (HS) group showed lower tumor mutation burden (TMB) and TP53 mutations and better prognosis than the low-score (LS) group. Lower immune infiltration, higher expression of PD-L1, PD-1, and CTLA4, and higher immune dysfunction and immune exclusion scores were identified in the LS group, suggesting a higher possibility of immune escape. Finally, the experimental verification shows that the m6A related genes, such as IGFBP1, plays an important role in the growth and metastasis of bladder cancer. CONCLUSIONS: These findings revealed the important roles of m6A MRGs in predicting prognosis, TMB status, TP53 mutation, immune functions and immunotherapeutic response in BC.

NFKBIE mutations are selected by the tumor microenvironment and contribute to immune escape in chronic lymphocytic leukemia.

Loss-of-function mutations in NFKBIE, which encodes for the NF-κB inhibitor IκBε, are frequent in chronic lymphocytic leukemia (CLL) and certain other B-cell malignancies and have been associated with accelerated disease progression and inferior responses to chemotherapy. Using in vitro and in vivo murine models and primary patient samples, we now show that NFKBIE-mutated CLL cells are selected by microenvironmental signals that activate the NF-κB pathway and induce alterations within the tumor microenvironment that can allow for immune escape, including expansion of CD8+ T-cells with an exhausted phenotype and increased PD-L1 expression on the malignant B-cells. Consistent with the latter observations, we find increased expression of exhaustion markers on T-cells from patients with NFKBIE-mutated CLL. In addition, we show that NFKBIE-mutated murine CLL cells display selective resistance to ibrutinib and report inferior outcomes to ibrutinib treatment in NFKBIE-mutated CLL patients. These findings suggest that NFKBIE mutations can contribute to CLL progression through multiple mechanisms, including a bidirectional crosstalk with the microenvironment and reduced sensitivity to BTK inhibitor treatment.

Emerging roles of TBK1 in cancer immunobiology.

TANK-binding kinase 1 (TBK1) is a versatile serine/threonine protein kinase with established roles in innate immunity, metabolism, autophagy, cell death, and inflammation. While best known for its role in regulating innate immunity, TBK1 has emerged as a cancer cell-intrinsic immune evasion gene by virtue of its role in modulating cellular responses to inflammatory signals emanating from the immune system. Beyond its effect on cancer cells, TBK1 appears to regulate lymphoid and myeloid cells in the tumor immune microenvironment. In this review, we detail recent advances in our understanding of the tumor-intrinsic and -extrinsic roles and regulation of TBK1 in tumor immunity.

Hepatitis B Virus-Mediated m6A Demethylation Increases Hepatocellular Carcinoma Stemness and Immune Escape.

Hepatitis B viral (HBV) persistent infection plays a significant role in hepatocellular carcinoma (HCC) tumorigenesis. Many studies have revealed the pivotal roles of N6-methyladenosine (m6A) in multiple cancers, while the regulatory mechanism in stemness maintenance of HBV persistent infection-related HCC remains elusive. Here, we demonstrated that the level of m6A modification was downregulated by HBV in HBV-positive HCC, through enhanced stability of ALKBH5 mRNA. More specifically, we also identified that ALKBH5 mRNA was functionally required for the stemness maintenance and self-renewal in the HBV-positive HCC, but dispensable in HBV-negative HCC. Mechanistically, ALKBH5 demethylated the m6A modification in the 3' untranslated region of the oncogenic gene SNAI2 to prevent the recognition of YTHDF2 therewith stabilize SNAI2 transcripts, contributing to cancer stem cell traits in HBV-positive HCC. Moreover, the expression of SNAI2 reversed the suppression of stemness properties by knocking down ALKBH5. In addition, ALKBH5/SNAI2 axis accelerates tumor immune evasion through activated ligand of immune checkpoint CD155. Our study unveiled that the ALKBH5 induces m6A demethylation of the SNAI2 as a key regulator in HBV-related HCC, and identifies the function of ALKBH5/SNAI2/YTHDF2 axis in promoting the stem-like cells phenotype and immune escape during HBV infection. IMPLICATIONS: HBV promotes HCC stemness maintenance through elevate m6A modification of SNAI2 in an ALKBH5-YTHDF2-dependent manner and increases the expression of the ligand of immune checkpoint CD155.

Regulatory T cell-mediated immunosuppression orchestrated by cancer: towards an immuno-genomic paradigm for precision medicine.

Accumulating evidence indicates that aberrant signalling stemming from genetic abnormalities in cancer cells has a fundamental role in their evasion of antitumour immunity. Immune escape mechanisms include enhanced expression of immunosuppressive molecules, such as immune-checkpoint proteins, and the accumulation of immunosuppressive cells, including regulatory T (Treg) cells, in the tumour microenvironment. Therefore, Treg cells are key targets for cancer immunotherapy. Given that therapies targeting molecules predominantly expressed by Treg cells, such as CD25 or GITR, have thus far had limited antitumour efficacy, elucidating how certain characteristics of cancer, particularly genetic abnormalities, influence Treg cells is necessary to develop novel immunotherapeutic strategies. Hence, Treg cell-targeted strategies based on the particular characteristics of cancer in each patient, such as the combination of immune-checkpoint inhibitors with molecularly targeted agents that disrupt the immunosuppressive networks mediating Treg cell recruitment and/or activation, could become a new paradigm of cancer therapy. In this Review, we discuss new insights on the mechanisms by which cancers generate immunosuppressive networks that attenuate antitumour immunity and how these networks confer resistance to cancer immunotherapy, with a focus on Treg cells. These insights lead us to propose the concept of 'immuno-genomic precision medicine' based on specific characteristics of cancer, especially genetic profiles, that correlate with particular mechanisms of tumour immune escape and might, therefore, inform the optimal choice of immunotherapy for individual patients.

The intricate dance of tumor evolution: Exploring immune escape, tumor migration, drug resistance, and treatment strategies.

Recent research has unveiled fascinating insights into the intricate mechanisms governing tumor evolution. These studies have illuminated how tumors adapt and proliferate by exploiting various factors, including immune evasion, resistance to therapeutic drugs, genetic mutations, and their ability to adapt to different environments. Furthermore, investigations into tumor heterogeneity and chromosomal aberrations have revealed the profound complexity that underlies the evolution of cancer. Emerging findings have also underscored the role of viral influences in the development and progression of cancer, introducing an additional layer of complexity to the field of oncology. Tumor evolution is a dynamic and complex process influenced by various factors, including immune evasion, drug resistance, tumor heterogeneity, and viral influences. Understanding these elements is indispensable for developing more effective treatments and advancing cancer therapies. A holistic approach to studying and addressing tumor evolution is crucial in the ongoing battle against cancer. The main goal of this comprehensive review is to explore the intricate relationship between tumor evolution and critical aspects of cancer biology. By delving into this complex interplay, we aim to provide a profound understanding of how tumors evolve, adapt, and respond to treatment strategies. This review underscores the pivotal importance of comprehending tumor evolution in shaping effective approaches to cancer treatment.

Molecular mechanism of specific HLA-A mRNA recognition by the RNA-binding-protein hMEX3B to promote tumor immune escape.

Immunotherapy, including immune checkpoint inhibitors and adoptive cell transfer, has obtained great progress, but their efficiencies vary among patients due to the genetic and epigenetic differences. Human MEX3B (hMEX3B) protein is an RNA-binding protein that contains two KH domains at the N-terminus and a RING domain at its C-terminus, which has the activity of E3 ubiquitin ligase and is essential for RNA degradation. Current evidence suggests that hMEX3B is involved in many important biological processes, including tumor immune evasion and HLA-A regulation, but the sequence of substrate RNA recognized by hMEX3B and the functional molecular mechanisms are unclear. Here, we first screened the optimized hMEX3B binding sequence on the HLA-A mRNA and reported that the two tandem KH domains can bind with their substrate one hundred times more than the individual KH domains. We systematically investigated the binding characteristics between the two KH domains and their RNA substrates by nuclear magnetic resonance (NMR). Based on this information and the small-angle X-ray scattering (SAXS) data, we used molecular dynamics simulations to obtain structural models of KH domains in complex with their corresponding RNAs. By analyzing the models, we noticed that on the KH domains' variable loops, there were two pairs of threonines and arginines that can disrupt the recognition of the RNA completely, and this influence had also been verified both in vitro and in vivo. Finally, we presented a functional model of the hMEX3B protein, which indicated that hMEX3B regulated the degradation of its substrate mRNAs in many biological processes. Taken together, our research illustrated how the hMEX3B protein played a key role in translation inhibition during the immune response to tumor cells and provided an idea and a lead for the study of the molecular mechanism and function of other MEX3 family proteins.

Mutant KRAS-activated circATXN7 fosters tumor immunoescape by sensitizing tumor-specific T cells to activation-induced cell death.

Mutant KRAS (KRASMUT) is often exploited by cancers to shape tumor immunity, but the underlying mechanisms are not fully understood. Here we report that tumor-specific cytotoxic T lymphocytes (CTLs) from KRASMUT cancers are sensitive to activation-induced cell death (AICD). circATXN7, an NF-κB-interacting circular RNA, governs T cell sensitivity to AICD by inactivating NF-κB. Mechanistically, histone lactylation derived from KRASMUT tumor cell-produced lactic acid directly activates transcription of circATXN7, which binds to NF-κB p65 subunit and masks the p65 nuclear localization signal motif, thereby sequestering it in the cytoplasm. Clinically, circATXN7 upregulation in tumor-specific CTLs correlates with adverse clinical outcomes and immunotherapeutic resistance. Genetic ablation of circAtxn7 in CD8+ T cells leads to mutant-selective tumor inhibition, while also increases anti-PD1 efficacy in multiple tumor models in female mice. Furthermore, targeting circATXN7 in adoptively transferred tumor-reactive CTLs improves their antitumor activities. These findings provide insight into how lymphocyte-expressed circRNAs contribute to T-cell fate decisions and anticancer immunotherapies.

Tumor immune evasion: insights from CRISPR screens and future directions.

Despite the clinical success of cancer immunotherapies including immune checkpoint blockade and adoptive cellular therapies across a variety of cancer types, many patients do not respond or ultimately relapse; however, the molecular underpinnings of this are not fully understood. Thus, a system-level understating of the routes to tumor immune evasion is required to inform the design of the next generation of immunotherapy approaches. CRISPR screening approaches have proved extremely powerful in identifying genes that promote tumor immune evasion or sensitize tumor cells to destruction by the immune system. These large-scale efforts have brought to light decades worth of fundamental immunology and have uncovered the key immune-evasion pathways subverted in cancers in an acquired manner in patients receiving immune-modulatory therapies. The comprehensive discovery of the main pathways involved in immune evasion has spurred the development and application of novel immune therapies to target this process. Although successful, conventional CRISPR screening approaches are hampered by a number of limitations, which obfuscate a complete understanding of the precise molecular regulation of immune evasion in cancer. Here, we provide a perspective on screening approaches to interrogate tumor-lymphocyte interactions and their limitations, and discuss further development of technologies to improve such approaches and discovery capability.

DCLK1 and its oncogenic functions: A promising therapeutic target for cancers.

Doublecortin-like kinase 1 (DCLK1), a significant constituent of the protein kinase superfamily and the doublecortin family, has been recognized as a prooncogenic factor that exhibits a strong association with the malignant progression and clinical prognosis of various cancers. DCLK1 serves as a stem cell marker that governs tumorigenesis, tumor cell reprogramming, and epithelial-mesenchymal transition. Multiple studies have indicated the capable of DCLK1 in regulating the DNA damage response and facilitating DNA damage repair. Additionally, DCLK1 is involved in the regulation of the immune microenvironment and the promotion of tumor immune evasion. Recently, DCLK1 has emerged as a promising therapeutic target for a multitude of cancers. Several small-molecule inhibitors of DCLK1 have been identified. Nevertheless, the biological roles of DCLK1 are mainly ambiguous, particularly with the disparities between its α- and ß-form transcripts in the malignant progression of cancers, which impedes the development of more precisely targeted drugs. This article focuses on tumor stem cells, tumor epithelial-mesenchymal transition, the DNA damage response, and the tumor microenvironment to provide a comprehensive overview of the association between DCLK1 and tumor malignant progression, address unsolved questions and current challenges, and project future directions for targeting DCLK1 for the diagnosis and treatment of cancers.