Esophageal cancer (ESCA) is defined by high incidence and mortality rates. Emerging evidence implicates angiopoietin‑2 (ANGPT2) as a key mediator in human carcinogenesis; however, its precise functional role and underlying mechanisms in ESCA remain incompletely elucidated. Clinical samples and The Cancer Genome Atlas, genotype‑tissue expression and Gene Expression Omnibus databases were first used to analyze ANGPT2 expression, clinical relevance and prognostic value, demonstrating it as an independent prognostic factor and potential oncogene in ESCA. In addition, abnormal ANGPT2 expression affected ESCA migration and invasion in vitro. Subsequently, through correlation, expression and prognostic analyses, the upstream long‑chain non‑coding RNAs and microRNAs that regulate ANGPT2 were identified. In conclusion, gene set enrichment analysis revealed a connection between ANGPT2 and the immune system, with ANGPT2 level showing a strong positive correlation with tumor microenvironment cell infiltration, immune cell markers, and immune checkpoint expression. Furthermore, ANGPT2 expression was significantly associated with sensitivity to chemotherapeutic drugs. To summarize, overexpression of ANGPT2 in ESCA is associated with an unfavorable prognosis and compromised tumor immunity.

Phosphatidylinositol 3-kinase (PI3K) phosphorylates PI(4,5)P2 to produce PI(3,4,5)P3, thereby activating AKT and other effector proteins. However, whether PI3K has non-PI(3,4,5)P3-related functions critical for tumor development remains unclear. Here, we demonstrate that high glucose induces PI3Kβ binding to O-linked β-D-N-acetylglucosamine (O-GlcNAc) transferase (OGT) in glioblastoma cells, dependent on hexokinase 1 (HK1)-mediated OGT Y889 phosphorylation and subsequent p85α recruitment. Importantly, PI3Kβ functions as a protein kinase, phosphorylating OGT at T985 and enhancing OGT activity and total cellular protein O-GlcNAcylation. Activated OGT O-GlcNAcylates ATP-citrate synthase (ACLY) at T639 and S667, leading to ACLY activation-dependent acetyl-coenzyme A (CoA) production to increase fatty acid levels and histone H3 acetylation for gene transcription. Intervention in PI3Kβ-mediated OGT phosphorylation and ACLY O-GlcNAcylation inhibits glioblastoma cell proliferation and tumor growth in xenografts. These findings underscore the critical role of PI3Kβ in governing protein O-GlcNAcylation, fatty acid metabolism, and chromatin modification through its protein kinase activity and provide instrumental insight into the roles of PI3K in tumor progression.

Background: To evaluate the efficacy and safety of allogenic CD8 + natural killer T (CD8+ NKT) immunotherapy combined with gefitinib in the treatment of advanced or metastatic EGFR mutant non-small cell lung cancer (NSCLC). Methods: This study is prospective. The NSCLC patients with exon 19 (Ex19del) or exon 21 L858R point mutations, and response to gefitinib treatment were enrolled into the trial to be randomly assigned into the gefitinib arm and the gefitinib/NKT arm. Allogenic CD8+ NKT cells were cultured in vitro and adaptive transferred into the patients via vein in the gefitinib/NKT arm. The primary endpoint was progression-free survival (PFS). Secondary endpoint analysis included time to disease progression (TTP), overall survival (OS), levels of serum tumour markers for carcinoembryonic antigen (CEA) and alanine aminotransferase (ALT) in the blood, the response rate and safety. From July 2017 to June 2021, 19 patients were randomly assigned to the gefitinib arm (n = 8) and the gefitinib/NKT arm (n = 11). Results: The estimated median survival PFS in the gefitinib/NKT arm was significantly longer than that of the gefitinib arm (12 months vs 7 months). Similar results were also observed for the median TTP. Moreover, the gefitinib/NKT arm had better CEA control than the gefitinib arm. Clinical grade 3 adverse reactions occurred in 64% and 39% of patients in the gefitinib/NKT arm and the gefitinib arm, respectively. The most common grade 3 adverse events in the gefitinib/NKT arm included abnormal liver function in 8 cases (73%) and diarrhoea in 1 case (9%), both of which resolved after drug intervention. Conclusion: The PFS of EGFR-mutated advanced NSCLC treated with allogenic CD8+ NKT cells combined with gefitinib was longer than that of gefitinib alone. No obvious serious adverse reactions occurred, and the patients compliance and survival status were good.

BACKGROUND:Ferroptosis is a distinct form of cell death characterized by unique morphology, biochemistry, and genetics, playing a crucial role in the initiation, progression, prognosis, and therapeutic strategies of tumors. However, the impact of ferroptosis-related genes (FRGs) on the tumor microenvironment (TME) remains unclear. This study may advance the existing knowledge of FRGs in gastric cancer, and push ahead with more effective prognostic assessment and the development of more effective immunotherapy approaches.METHODS:FRGs were acquired from the FerrDb database and a consensus clustering technique was adopted to categorize patients with GC into groups in line with the expression profiles of 44 FRGs in order to further investigate the expression properties of these proteins. Assessment of the immune status, microsatellite instability (MSI) and cancer stem cell (CSC) index between the high- and low- risk groups to assess the proportion of TIICs in the TME, ssGSVA was adopted to detect the abundance of infiltrating immune cells from the low-risk and high-risk groups. Expression levels of eight ferroptosis-related genes of prognostic signature in GC tissues and adjacent normal tissues was detected by RT-PCR.RESULTS:In the GC cohort, TP53 has the highest mutation frequency (44 %), and was shown to be highly linked with the expression levels of 11 FRGs. In accordance with the Kaplan-Meier curve, the overall survival time of patients with subtype A (Low FRG-score) discernibly exceeded that of patients with subtype B (High FRG-score).In addition, there is a significant difference in the infiltration of most immune cells between subtype A and subtype B, and some important immune checkpoints (CTLA4, PDCD1, CD274, LAG3, PDCD1LG2, and HAVCR2) have higher expression in cluster A. Finally, low FRG-scores were significantly associated with MSI-H status, while high FRG-scores were significantly associated with microsatellite stable status (MSS). FRG-score is negatively related to the cancer stem cell (CSC).CONCLUSION:Low FRG-score, due to its high microsatellite instability (MSI-H), high mutational load and immune activation, indicates the possible advantage of OS. In addition, the FRG-score was closely related to the cancer stem cell (CSC) index and the sensitive degree of chemotherapeutic drug.

目的 评估低剂量阿帕替尼联合热疗应用于二线治疗失败后的晚期胃癌患者的临床疗效和安全性.方法 随机选取2020年12月—2021年12月扬州大学附属靖江市人民医院收治的80例二线治疗失败的晚期胃癌患者为研究对象,根据随机数表法分为联合组和靶向治疗组,各40例,靶向治疗组患者口服阿帕替尼250 mg/d治疗,联合组患者在对照组基础上联合热疗,观察两组患者的临床疗效、不良反应、KPS及癌痛评分.结果 联合组DCR(90.0％)优于靶向治疗组(72.5％),差异有统计学意义(χ2=4.021,P=0.045).联合组与靶向治疗组的不良反应发生率比较,差异无统计学意义(P>0.05).联合组KPS评分好转率(65.0％)优于靶向治疗组(37.5％),差异有统计学意义(χ2=6.054,P=0.014).联合组癌痛评分低于靶向治疗组,差异有统计学意义(P<0.001).结论 对于晚期的胃癌患者采用口服低剂量阿帕替尼联合热疗具有较好的临床治疗效果,且不良反应发生率低,能够确保抗肿瘤治疗的有效性和安全性,可作为临床晚期胃癌患者的一种治疗选择.

Solute carrier family 7 member 11 (SLC7A11) is a major transporter regulating cysteine metabolism and is widely expressed in a variety of tumor cells. SLC7A11 plays an important role in the occurrence, development, invasion and metastasis of tumors by regulating the transport of cysteine in the tumor microenvironment. SLC7A11 is expected to become a new therapeutic target and prognostic indicator for the individualized treatment of patients. According to relevant research reports, SLC7A11 can predict the stages and metastasis of liver, breast and lung cancer. Therefore, an in-depth exploration of the role of SLC7A11 in tumors may be important for the screening, early diagnosis, treatment and prognosis of patients with tumors. The current review summarizes the research progress on SLC7A11 in liver cancer, lung cancer and other tumors on the basis of previous primary studies. In addition, the present review systematically elaborates on the three main aspects of SLC7A11 pathways in some tumors, the cancer-promoting mechanisms, and the therapeutic relationship between SLC7A11 and tumors. Finally, the present review aims to provide a reference for assessing whether SLC7A11 can be used as a prognostic indicator and treatment target for tumor patients, and the future research direction with regard to SLC7A11 in tumors.

Acetyl-CoA Synthetase 2 (ACSS2) belongs to a member of the acyl-CoA short-chain synthase family, which can convert acetate in the cytoplasm and nucleus into acetyl-CoA. It has been proven that ACSS2 is highly expressed in glioblastoma, breast cancer, liver cancer, prostate cancer, bladder cancer, renal cancer, and other tumors, and is closely related to tumor stage and the overall survival rate of patients. Accumulating studies show that hypoxia and a low serum level induce ACSS2 expression to help tumor cells cope with this nutrient-poor environment. The potential mechanisms are associated with the ability of ACSS2 to promote the synthesis of lipids in the cytoplasm, induce the acetylation of histones in the nucleus, and facilitate the expression of autophagy genes. Novel-specific inhibitors of ACSS2 are developed and confirmed to the effectiveness in pre-clinical tumor models. Targeting ACSS2 may provide novel approaches for tumor treatment. This review summarizes the biological function of ACSS2, its relation to survival and prognosis in different tumors, and how ACSS2 mediates different pathways to promote tumor metastasis, invasion, and drug resistance.

Angiopoietin-2 (Ang2), a member of the angiopoietin family, is widely involved in the process of vascular physiology, bone physiology, adipose tissue physiology and the occurrence and development of inflammation, cardiac hypertrophy, rheumatoid, tumor and other diseases under pathological conditions. Proliferation and metastasis of cancer largely depend on angiogenesis. Therefore, anti-angiogenesis has become the target of tumor therapy. Due to the Ang2 plays a key role in promoting angiogenesis and stability in vascular physiology, the imbalance of its expression is an important condition for the occurrence and development of cancer. It has been proved that blocking Ang2 can inhibit the growth, invasion and metastasis of cancer cells. In recent years, research has been constantly supplemented. We focus on the mechanisms that regulate the expression of Ang2 mRNA and protein levels in different cancers, contributing to a better understanding of how Ang2 exerts different effects in different cancers and stages, as well as facilitating more specific targeting of relevant molecules in cancer therapy. At the same time, the importance of Ang2 in cancer growth, metastasis, prognosis and combination therapy is pointed out. And finally, we will discuss the current investigations and future challenges of combining Ang2 inhibition with chemotherapy, immunotherapy, and radiotherapy to increase its efficacy in cancer patients. This review provides a theoretical reference for the development of new targets and effective combination therapy strategies for cancer treatment in the future.

Gefitinib has shown good efficacy in patients with EGFR mutation-positive non-small-cell lung cancer, but acquired resistance is inevitable. Here we report a patient with an advanced lung adenocarcinoma with the EGFR mutation who achieved surgical opportunity and long-term survival following treatment with chemotherapy and bevacizumab, followed by sequential gefitinib combined with allogeneic haploidentical CD8+ CD56+ natural killer T cells. Our case provides a potential effective strategy for delaying acquired gefitinib resistance and extending progression-free survival among patients with non-small-cell lung cancer who harbor common EGFR mutations.

Bromodomain-containing protein 4 (BRD4), a member of the bromodomain and extraterminal (BET) family, is considered to be a major driver of cancer cell growth and a new target for cancer therapy. Over 30 targeted inhibitors currently in preclinical and clinical trials have significant inhibitory effects on various tumors, including acute myelogenous leukemia (AML), diffuse large B cell lymphoma, prostate cancer, breast cancer and so on. However, resistance frequently occurs, revealing the limitations of BET inhibitor (BETi) therapy and the complexity of the BRD4 expression mechanism and action pathway. Current studies believe that when the internal and external environmental conditions of cells change, tumor cells can directly modify proteins by posttranslational modifications (PTMs) without changing the original DNA sequence to change their functions, and epigenetic modifications can also be activated to form new heritable phenotypes in response to various environmental stresses. In fact, research is constantly being supplemented with regards to that the regulatory role of BRD4 in tumors is closely related to PTMs. At present, the PTMs of BRD4 mainly include ubiquitination and phosphorylation; the former mainly regulates the stability of the BRD4 protein and mediates BETi resistance, while the latter is related to the biological functions of BRD4, such as transcriptional regulation, cofactor recruitment, chromatin binding and so on. At the same time, other PTMs, such as hydroxylation, acetylation and methylation, also play various roles in BRD4 regulation. The diversity, complexity and reversibility of posttranslational modifications affect the structure, stability and biological function of the BRD4 protein and participate in the occurrence and development of tumors by regulating the expression of tumor-related genes and even become the core and undeniable mechanism. Therefore, targeting BRD4-related modification sites or enzymes may be an effective strategy for cancer prevention and treatment. This review summarizes the role of different BRD4 modification types, elucidates the pathogenesis in the corresponding cancers, provides a theoretical reference for identifying new targets and effective combination therapy strategies, and discusses the opportunities, barriers, and limitations of PTM-based therapies for future cancer treatment.

磷酸赖氨酸磷酸组氨酸无机焦磷酸盐磷酸酶(LHPP)是调控组氨酸去磷酸化的重要的酶,主要在肝、脑、肾组织中表达,其与组氨酸激酶共同调控组氨酸残基的磷酸化与去磷酸化,该酶的缺失可破坏组氨酸残基的磷酸化与去磷酸化的平衡,导致PI3K/Akt、Wnt/β-catenin等一系列信号通路的异常活化,进而引起细胞周期蛋白、凋亡蛋白的异常,促进肿瘤的发生发展.LHPP对于肿瘤患者的早期筛查、早期诊断和治疗及预后具有重要意义,并有望成为患者个体化治疗的新治疗靶点和预后指标.本综述在以往文献研究的基础上,对LHPP在肝癌、胶质瘤、肾癌等部分肿瘤中的作用的研究进展进行了总结,旨在为LHPP在肿瘤中未来的研究方向和应用提供参考.

Acetyl-CoA synthetase 2 (ACSS2), an important member of the acetyl-CoA synthetase (ACSS) family, can catalyze the conversion of acetate to acetyl coenzyme A (acetyl-CoA). Currently, acetyl-CoA is considered an important intermediate metabolite in the metabolism of energy substrates. In addition, nutrients converge through acetyl-CoA into a common metabolic pathway, the tricarboxylic acid cycle and oxidative phosphorylation. Not only does ACSS2 play a crucial role in material energy metabolism, it is also involved in the regulation of various acetylation processes, such as regulation of histone and transcription factor acetylation. ACSS2-mediated regulation of acetylation is related to substance metabolism and tumorigenesis. In mammalian cells, ACSS2 utilizes intracellular acetate to synthesize acetyl-CoA, a step in the process of DNA and histone acetylation. In addition, studies in tumors have shown that cancer cells adapt to the growth conditions in the tumor microenvironment (TME) by activating or increasing the expression level of ACSS2 under metabolic stress. Therefore, this review mainly outlines the role of ACSS2 in substance metabolism and tumors and provides insights useful for investigating ACSS2 as a therapeutic target.

Angiopoietin-2 (Ang2), a member of the angiopoietin family, is widely involved in the process of vascular physiology, bone physiology, adipose tissue physiology and the occurrence and development of inflammation, cardiac hypertrophy, rheumatoid, tumor and other diseases under pathological conditions. Proliferation and metastasis of cancer largely depend on angiogenesis. Therefore, anti-angiogenesis has become the target of tumor therapy. Due to the Ang2 plays a key role in promoting angiogenesis and stability in vascular physiology, the imbalance of its expression is an important condition for the occurrence and development of cancer. It has been proved that blocking Ang2 can inhibit the growth, invasion and metastasis of cancer cells. In recent years, research has been constantly supplemented. We focus on the mechanisms that regulate the expression of Ang2 mRNA and protein levels in different cancers, contributing to a better understanding of how Ang2 exerts different effects in different cancers and stages, as well as facilitating more specific targeting of relevant molecules in cancer therapy. At the same time, the importance of Ang2 in cancer growth, metastasis, prognosis and combination therapy is pointed out. And finally, we will discuss the current investigations and future challenges of combining Ang2 inhibition with chemotherapy, immunotherapy, and radiotherapy to increase its efficacy in cancer patients. This review provides a theoretical reference for the development of new targets and effective combination therapy strategies for cancer treatment in the future.

雌激素相关肿瘤是女性较为常见的恶性肿瘤类型.绝经前妇女雌激素主要由卵巢分泌,而绝经后雌激素的重要来源为芳香化酶催化雄激素转化为雌激素,因此芳香化酶抑制剂(aromatase inhibitors,AIs)作为绝经后乳腺癌、子宫内膜癌和上皮性卵巢癌的治疗药物在临床上得到广泛应用.AIs的使用会带来多种不良后果,如潮热、骨痛、骨质疏松和增加心血管疾病的风险等,但其引起的代谢失衡尤为重要.本文综述AIs治疗后可能带来的代谢失衡,分析代谢紊乱发生的原因,提出了采用联合使用二甲双胍和联合运动的方式改善AIs治疗雌激素相关肿瘤所致代谢失衡的新思路.

PurposeTo incorporate the bilateral filtering into the Deformable Vector Field (DVF) based 4D-CBCT reconstruction for realizing a fully automatic sliding motion compensated 4D-CBCT.Materials and MethodsInitially, a motion compensated simultaneous algebraic reconstruction technique (mSART) is used to generate a high quality reference phase (e.g. 0% phase) by using all phase projections together with the initial 4D-DVFs. The initial 4D-DVF were generated via Demons registration between 0% phase and each other phase image. The 4D-DVF will then kept updating by matching the forward projection of the deformed high quality 0% phase with the measured projection of the target phase. The loss function during this optimization contains an projection intensity difference matching criterion plus a DVF smoothing constrain term. We introduce a bilateral filtering kernel into the DVF constrain term to estimate the sliding motion automatically. The bilateral filtering kernel contains three sub-kernels: 1) an spatial domain Guassian kernel; 2) an image intensity domain Guassian kernel; and 3) a DVF domain Guassian kernel. By choosing suitable kernel variances, the sliding motion can be extracted. A non-linear conjugate gradient optimizer was used. We validated the algorithm on a non-uniform rotational B-spline based cardiac-torso (NCAT) phantom and four anonymous patient data. For quantification, we used: 1) the Root-Mean-Square-Error (RMSE) together with the Maximum-Error (MaxE); 2) the Dice coefficient of the extracted lung contour from the final reconstructed images and 3) the relative reconstruction error (RE) to evaluate the algorithm's performance.ResultsFor NCAT phantom, the motion trajectory's RMSE/MaxE are 0.796/1.02 mm for bilateral filtering reconstruction; and 2.704/4.08 mm for original reconstruction. For patient pilot study, the 4D-Dice coefficient obtained with bilateral filtering are consistently higher than that without bilateral filtering. Meantime several image content such as the rib position, the heart edge definition, the fibrous structures all has been better corrected with bilateral filtering.ConclusionWe developed a bilateral filtering based fully automatic sliding motion compensated 4D-CBCT scheme. Both digital phantom and initial patient pilot studies confirmed the improved motion estimation and image reconstruction ability. It can be used as a 4D-CBCT image guidance tool for lung SBRT treatment.

The low sensitivity of radiotherapy is the main cause of tumor tolerance against ionizing radiation (IR). However, the molecular mechanisms by which radiosensitivity is controlled remain elusive. Here, we observed that high expression of pellino E3 ubiquitin protein ligase 1 (PELI1) was correlated with improved prognosis in human esophageal squamous cell carcinoma stage III patients that received adjuvant radiotherapy. Moreover, we found PELI1‐mediated IR‐induced tumor cell apoptosis in vivo and in vitro. Mechanistically, PELI1 mediated the lysine 48 (Lys48)–linked polyubiquitination and degradation of NF‐κB–inducing kinase (NIK; also known as MAP3K14), the master kinase of the noncanonical NF‐κB pathway, thereby inhibiting IR‐induced activation of the noncanonical NF‐κB signaling pathway during radiotherapy. As a consequence, PELI1 inhibited the noncanonical NF‐κB–induced expression of the anti‐apoptotic gene BCL2 like 1 (Bclxl; also known as BCL2L1), leading to an enhancement of the IR‐induced apoptosis signaling pathway and ultimately promoting IR‐induced apoptosis in tumor cells. Therefore, Bclxl or NIK knockdown abolished the apoptosis‐resistant effect in PELI1‐knockdown tumor cells after radiotherapy. These findings establish PELI1 as a critical tumor intrinsic regulator in controlling the sensitivity of tumor cells to radiotherapy through modulating IR‐induced noncanonical NF‐κB expression.

Poly(β-L-malic acid) (PMLA) is a natural polyester produced by numerous microorganisms. Regarding its biosynthetic machinery, a nonribosomal peptide synthetase (NRPS) is proposed to direct polymerization of L-malic acid in vivo. Chemically versatile and biologically compatible, PMLA can be used as an ideal carrier for several molecules, including nucleotides, proteins, chemotherapeutic drugs, and imaging agents, and can deliver multimodal theranostics through biological barriers such as the blood-brain barrier. We focus on PMLA biosynthesis in microorganisms, summarize the physicochemical and physiochemical characteristics of PMLA as a naturally derived polymeric delivery platform at nanoscale, and highlight the attachment of functional groups to enhance cancer detection and treatment.

The low sensitivity of radiotherapy is the main cause of tumor tolerance against ionizing radiation (IR). However, the molecular mechanisms by which radiosensitivity is controlled remain elusive. Here, we observed that high expression of pellino E3 ubiquitin protein ligase 1 (PELI1) was correlated with improved prognosis in human esophageal squamous cell carcinoma stage III patients that received adjuvant radiotherapy. Moreover, we found PELI1‐mediated IR‐induced tumor cell apoptosis in vivo and in vitro. Mechanistically, PELI1 mediated the lysine 48 (Lys48)–linked polyubiquitination and degradation of NF‐κB–inducing kinase (NIK; also known as MAP3K14), the master kinase of the noncanonical NF‐κB pathway, thereby inhibiting IR‐induced activation of the noncanonical NF‐κB signaling pathway during radiotherapy. As a consequence, PELI1 inhibited the noncanonical NF‐κB–induced expression of the anti‐apoptotic gene BCL2 like 1 (Bclxl; also known as BCL2L1), leading to an enhancement of the IR‐induced apoptosis signaling pathway and ultimately promoting IR‐induced apoptosis in tumor cells. Therefore, Bclxl or NIK knockdown abolished the apoptosis‐resistant effect in PELI1‐knockdown tumor cells after radiotherapy. These findings establish PELI1 as a critical tumor intrinsic regulator in controlling the sensitivity of tumor cells to radiotherapy through modulating IR‐induced noncanonical NF‐κB expression.

Solute carrier family 7 member 11 (SLC7A11) is a major transporter regulating cysteine metabolism and is widely expressed in a variety of tumor cells. SLC7A11 plays an important role in the occurrence, development, invasion and metastasis of tumors by regulating the transport of cysteine in the tumor microenvironment. SLC7A11 is expected to become a new therapeutic target and prognostic indicator for the individualized treatment of patients. According to relevant research reports, SLC7A11 can predict the stages and metastasis of liver, breast and lung cancer. Therefore, an in-depth exploration of the role of SLC7A11 in tumors may be important for the screening, early diagnosis, treatment and prognosis of patients with tumors. The current review summarizes the research progress on SLC7A11 in liver cancer, lung cancer and other tumors on the basis of previous primary studies. In addition, the present review systematically elaborates on the three main aspects of SLC7A11 pathways in some tumors, the cancer-promoting mechanisms, and the therapeutic relationship between SLC7A11 and tumors. Finally, the present review aims to provide a reference for assessing whether SLC7A11 can be used as a prognostic indicator and treatment target for tumor patients, and the future research direction with regard to SLC7A11 in tumors.

The immunosuppressive microenvironment that is shaped by hepatic metastatic pancreatic ductal adenocarcinoma (PDAC) is essential for tumor cell evasion of immune destruction. Neutrophils are important components of the metastatic tumor microenvironment and exhibit heterogeneity. However, the specific phenotypes, functions and regulatory mechanisms of neutrophils in PDAC liver metastases remain unknown. Here, we show that a subset of P2RX1-negative neutrophils accumulate in clinical and murine PDAC liver metastases. RNA sequencing of murine PDAC liver metastasis-infiltrated neutrophils show that P2RX1-deficient neutrophils express increased levels of immunosuppressive molecules, including PD-L1, and have enhanced mitochondrial metabolism. Mechanistically, the transcription factor Nrf2 is upregulated in P2RX1-deficient neutrophils and associated with PD-L1 expression and metabolic reprogramming. An anti-PD-1 neutralizing antibody is sufficient to compromise the immunosuppressive effects of P2RX1-deficient neutrophils on OVA-activated OT1 CD8+ T cells. Therefore, our study uncovers a mechanism by which metastatic PDAC tumors evade antitumor immunity by accumulating a subset of immunosuppressive P2RX1-negative neutrophils.