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Despite great success in cancer immunotherapy, immune checkpoint-targeting drugs are not the most popular weapon in the armory of cancer therapy. Accumulating evidence suggests that the tumor immune microenvironment plays a critical role in anti-cancer immunity, which may result in immune checkpoint blockade therapy being ineffective, in addition to other novel immunotherapies in cancer patients. In the present review, we discuss the deficiencies of current cancer immunotherapies. More importantly, we highlight the critical role of tumor immune microenvironment regulators in tumor immune surveillance, immunological evasion, and the potential for their further translation into clinical practice. Based on their general targetability in clinical therapy, we believe that tumor immune microenvironment regulators are promising cancer immunotherapeutic targets. Targeting the tumor immune microenvironment, alone or in combination with immune checkpoint-targeting drugs, might benefit cancer patients in the future.

Despite the substantial impact of post-translational modifications on programmed cell death 1 ligand 1 (PD-L1), its importance in therapeutic resistance in pancreatic cancer remains poorly defined. Here, we demonstrate that never in mitosis gene A-related kinase 2 (NEK2) phosphorylates PD-L1 to maintain its stability, causing PD-L1-targeted pancreatic cancer immunotherapy to have poor efficacy. We identify NEK2 as a prognostic factor in immunologically “hot” pancreatic cancer, involved in the onset and development of pancreatic tumors in an immune-dependent manner. NEK2 deficiency results in the suppression of PD-L1 expression and enhancement of lymphocyte infiltration. A NEK binding motif (F/LXXS/T) is identified in the glycosylation-rich region of PD-L1. NEK2 interacts with PD-L1, phosphorylating the T194/T210 residues and preventing ubiquitin-proteasome pathway-mediated degradation of PD-L1 in ER lumen. NEK2 inhibition thereby sensitizes PD-L1 blockade, synergically enhancing the anti-pancreatic cancer immune response. Together, the present study proposes a promising strategy for improving the effectiveness of pancreatic cancer immunotherapy. NEK2 is a serine-threonine kinase overexpressed in a variety of human cancers. Here the authors show that NEK2 controls the stability of PD-L1 by preventing its proteasome-mediated degradation and that NEK2 targeting restores anti-tumor immune responses in preclinical models of pancreatic cancer.

O -linked β- d - N -acetylglucosamine ( O -GlcNAc) is an important post-translational modification of serine or threonine residues on thousands of proteins in the nucleus and cytoplasm of all animals and plants. In eukaryotes, only two conserved enzymes are involved in this process. O -GlcNAc transferase is responsible for adding O -GlcNAc to proteins, while O -GlcNAcase is responsible for removing it. Aberrant O -GlcNAcylation is associated with a variety of human diseases, such as diabetes, cancer, neurodegenerative diseases, and cardiovascular diseases. Numerous studies have confirmed that O -GlcNAcylation is involved in the occurrence and progression of cancers in multiple systems throughout the body. It is also involved in regulating multiple cancer hallmarks, such as metabolic reprogramming, proliferation, invasion, metastasis, and angiogenesis. In this review, we first describe the process of O -GlcNAcylation and the structure and function of O -GlcNAc cycling enzymes. In addition, we detail the occurrence of O -GlcNAc in various cancers and the role it plays. Finally, we discuss the potential of O -GlcNAc as a promising biomarker and novel therapeutic target for cancer diagnosis, treatment, and prognosis.

VISTA (V-domain immunoglobulin suppressor of T cell activation) is a well-established immune regulatory receptor. However, pre-clinical investigations indicated more complicated influences of VISTA on cancer immunity than previously recognized. Here, we review the current knowledge on the therapeutic phenotypes and molecular mechanisms that underlie the contradictory roles of VISTA in checking anti-cancer immune responses. Furthermore, we highlight the potential indeterminacy of VISTA-targeted strategies in cancer immunotherapy, with in silico analyses. In fact, VISTA functions like a homeostatic regulator that actively normalizes immune responses. Thus, the regulatory role of VISTA in anti-cancer immunity remains to be fully elucidated.

Single-cell analysis is a valuable tool for dissecting cellular heterogeneity in complex systems 1 . However, a comprehensive single-cell atlas has not been achieved for humans. Here we use single-cell mRNA sequencing to determine the cell-type composition of all major human organs and construct a scheme for the human cell landscape (HCL). We have uncovered a single-cell hierarchy for many tissues that have not been well characterized. We established a ‘single-cell HCL analysis’ pipeline that helps to define human cell identity. Finally, we performed a single-cell comparative analysis of landscapes from human and mouse to identify conserved genetic networks. We found that stem and progenitor cells exhibit strong transcriptomic stochasticity, whereas differentiated cells are more distinct. Our results provide a useful resource for the study of human biology. Single-cell RNA sequencing is used to generate a dataset covering all major human organs in both adult and fetal stages, enabling comparison with similar datasets for mouse tissues.

This study addresses the problem of inaccurate channel flow simulation and uneven irrigation water distribution caused by the spatiotemporal variability of Manning’s roughness coefficient. The SCE-UA optimization algorithm was applied to calibrate Manning’s roughness coefficients and quantify their spatiotemporal variation patterns using 1728 sets of measured water level–discharge data collected in the Yellow River Irrigation District. Results show that accounting for spatiotemporal variability reduces the mean absolute percentage error (MAPE) for water level simulation by nearly 8%. Based on these findings, an automatic roughness update system specifically designed for grassroots water distribution stations has been developed, which can integrate water demand and gate control to achieve efficient water allocation in canals in the future.

Mortality associated with pancreatic cancer is among the highest of all malignancies, with a 5-year overall survival of 5–10%. Immunotherapy, represented by the blocking antibodies against programmed cell death protein 1 or its ligand 1 (anti-PD-(L)1), has achieved remarkable success in a number of malignancies. However, due to the immune-suppressive tumor microenvironment, the therapeutic efficacy of anti-PD-(L)1 in pancreatic cancer is far from expectation. To address such a fundamental issue, chemotherapy, radiotherapy, targeted therapy and even immunotherapy itself, have individually been attempted to combine with anti-PD-(L)1 in preclinical and clinical investigation. This review, with a particular focus on pancreatic cancer therapy, collects current anti-PD-(L)1-based combination strategy, highlights potential adverse effects of accumulative combination, and further points out future direction in optimization of combination, including targeting post-translational modification of PD-(L)1 and improving precision of treatment.

Metabolic reprogramming shapes the tumor microenvironment (TME) and may lead to immunotherapy resistance in pancreatic ductal adenocarcinoma (PDAC). Elucidating the impact of pancreatic cancer cell metabolism in the TME is essential to therapeutic interventions. “Immune cold” PDAC is characterized by elevated lactate levels resulting from tumor cell metabolism, abundance of protumor macrophages, and reduced cytotoxic T cells in the TME. Analysis of fluorine-18 fluorodeoxyglucose ( 18 F-FDG) uptake in patients showed that increased global protein lactylation in PDAC correlates with worse clinical outcomes in immunotherapy. Inhibition of lactate production in pancreatic tumors via glycolysis or mutant-KRAS inhibition reshaped the TME, thereby increasing their sensitivity to immune checkpoint blockade (ICB) therapy. In pancreatic tumor cells, lactate induces K63 lactylation of endosulfine α (ENSA-K63la), a crucial step that triggers STAT3/CCL2 signaling. Consequently, elevated CCL2 secreted by tumor cells facilitates tumor-associated macrophage (TAM) recruitment to the TME. High levels of lactate also drive transcriptional reprogramming in TAMs via ENSA-STAT3 signaling, promoting an immunosuppressive environment. Targeting ENSA-K63la or CCL2 enhances the efficacy of ICB therapy in murine and humanized pancreatic tumor models. In conclusion, elevated lactylation reshapes the TME and promotes immunotherapy resistance in PDAC. A therapeutic approach targeting ENSA-K63la or CCL2 has shown promise in sensitizing pancreatic cancer immunotherapy.

Macrophages exist in most tissues of the body, where they perform various functions at the same time equilibrating with other cells to maintain immune responses in numerous diseases including cancer. Recently, emerging investigations revealed that metabolism profiles control macrophage phenotypes and functions, and in turn, polarization can trigger metabolic shifts in macrophages. Those findings implicate a special role of metabolism in tumor-associated macrophages (TAMs) because of the sophisticated microenvironment in cancer. Glucose is the major energy source of cells, especially for TAMs. However, the complicated association between TAMs and their glucose metabolism is still unclearly illustrated. Here, we review the recent advances in macrophage and glucose metabolism within the tumor microenvironment, and the significant transformations that occur in TAMs during the tumor progression. Additionally, we have also outlined the potential implications for macrophage-based therapies in cancer targeting TAMs.

Amino acids are pivotal regulators of immune cell metabolism, signaling pathways, and gene expression. In myeloid cells, these processes underlie their functional plasticity, enabling shifts between pro-inflammatory, anti-inflammatory, pro-tumor, and anti-tumor activities. Within the tumor microenvironment, amino acid metabolism plays a crucial role in mediating the immunosuppressive functions of myeloid cells, contributing to tumor progression. This review delves into the mechanisms by which specific amino acids—glutamine, serine, arginine, and tryptophan—regulate myeloid cell function and polarization. Furthermore, we explore the therapeutic potential of targeting amino acid metabolism to enhance anti-tumor immunity, offering insights into novel strategies for cancer treatment.