: Glycoprotein prostaglandin D2 synthase (PTGDS) is a member of the lipocalin superfamily and plays dual roles in prostaglandins metabolism and lipid transport. PTGDS has been involved in various cellular processes including the tumorigenesis of solid tumors, yet its role in carcinogenesis is contradictory and the significance of PTGDS in hematological malignancies is ill-defined. Here, we aimed to explore the expression and function of PTGDS in diffuse large B-cell lymphoma (DLBCL), especially the potential role of PTGDS inhibitor, AT56, in lymphoma therapy. Remarkable high expression of PTGDS was found in DLBCL, which was significantly correlated with poor prognosis. PTGDS overexpression and rhPTGDS were found to promote cell proliferation. Besides, in vitro and in vivo studies indicated that PTGDS knockdown and AT56 treatment exerted an anti-tumor effect by regulating cell viability, proliferation, apoptosis, cell cycle, and invasion, and enhanced the drug sensitivity to adriamycin and bendamustine through promoting DNA damage. Moreover, the co-immunoprecipitation-based mass spectrum identified the interaction between PTGDS and MYH9, which was found to promote DLBCL progression. PTGDS inhibition led to reduced expression of MYH9, and then declined activation of the Wnt-β-catenin-STAT3 pathway through influencing the ubiquitination and degradation of GSK3-β in DLBCL. The rescue experiment demonstrated that PTGDS exerted an oncogenic role through regulating MYH9 and then the Wnt-β-catenin-STAT3 pathway. Based on point mutation of glycosylation sites, we confirmed the N-glycosylation of PTGDS in Asn51 and Asn78 and found that abnormal glycosylation of PTGDS resulted in its nuclear translocation, prolonged half-life, and enhanced cell proliferation. Collectively, our findings identified for the first time that glycoprotein PTGDS promoted tumorigenesis of DLBCL through MYH9-mediated regulation of Wnt-β-catenin-STAT3 signaling, and highlighted the potential role of AT56 as a novel therapeutic strategy for DLBCL treatment.

Metabolic reprogramming has been demonstrated to have a significant impact on the biological behaviors of tumor cells, among which glycolysis is an important form. Recent research has revealed that the heightened glycolysis levels, the abnormal expression of glycolytic enzymes, and the accumulation of glycolytic products could regulate the growth, proliferation, invasion, and metastasis of tumor cells and provide a favorable microenvironment for tumor development and progression. Based on the distinctive glycolytic characteristics of tumor cells, novel imaging tests have been developed to evaluate tumor proliferation and metastasis. In addition, glycolytic enzymes have been found to serve as promising biomarkers in tumor, which could provide assistance in the early diagnosis and prognostic assessment of tumor patients. Numerous glycolytic enzymes have been identified as potential therapeutic targets for tumor treatment, and various small molecule inhibitors targeting glycolytic enzymes have been developed to inhibit tumor development and some of them are already applied in the clinic. In this review, we systematically summarized recent advances of the regulatory roles of glycolysis in tumor progression and highlighted the potential clinical significance of glycolytic enzymes and products as novel biomarkers and therapeutic targets in tumor treatment.

Immune checkpoints are differentially expressed on various immune cells to regulate immune responses in tumor microenvironment. Tumor cells can activate the immune checkpoint pathway to establish an immunosuppressive tumor microenvironment and inhibit the anti‐tumor immune response, which may lead to tumor progression by evading immune surveillance. Interrupting co‐inhibitory signaling pathways with immune checkpoint inhibitors (ICIs) could reinvigorate the anti‐tumor immune response and promote immune‐mediated eradication of tumor cells. As a milestone in tumor treatment, ICIs have been firstly used in solid tumors and subsequently expanded to hematological malignancies, which are in their infancy. Currently, immune checkpoints have been investigated as promising biomarkers and therapeutic targets in hematological malignancies, and novel immune checkpoints, such as signal regulatory protein α (SIRPα) and tumor necrosis factor‐alpha‐inducible protein 8‐like 2 (TIPE2), are constantly being discovered. Numerous ICIs have received clinical approval for clinical application in the treatment of hematological malignancies, especially when used in combination with other strategies, including oncolytic viruses (OVs), neoantigen vaccines, bispecific antibodies (bsAb), bio‐nanomaterials, tumor vaccines, and cytokine‐induced killer (CIK) cells. Moreover, the proportion of individuals with hematological malignancies benefiting from ICIs remains lower than expected due to multiple mechanisms of drug resistance and immune‐related adverse events (irAEs). Close monitoring and appropriate intervention are needed to mitigate irAEs while using ICIs. This review provided a comprehensive overview of immune checkpoints on different immune cells, the latest advances of ICIs and highlighted the clinical applications of immune checkpoints in hematological malignancies, including biomarkers, targets, combination of ICIs with other therapies, mechanisms of resistance to ICIs, and irAEs, which can provide novel insight into the future exploration of ICIs in tumor treatment.

Natural killer (NK) cell belongs to innate lymphoid cell family that contributes to host immunosurveillance and defense without pre-immunization. Emerging studies have sought to understand the underlying mechanism behind NK cell dysfunction in tumor environments, and provide numerous novel therapeutic targets for tumor treatment. Strategies to enhance functional activities of NK cell have exhibited promising efficacy and favorable tolerance in clinical treatment of tumor patients, such as immune checkpoint blockade (ICB), chimeric antigen receptor NK (CAR-NK) cell, and bi/trispecific killer cell engager (BiKE/TriKE). Immunotherapy targeting NK cell provides remarkable advantages compared to T cell therapy, including a decreased rate of graft versus-host disease (GvHD) and neurotoxicity. Nevertheless, advanced details on how to support the maintenance and function of NK cell to obtain better response rate and longer duration still remain to be elucidated. This review systematically summarizes the profound role of NK cells in tumor development, highlights up-to-date advances and current challenges of therapy targeting NK cell in the clinical treatment of hematologic malignancies.

Single-cell technologies have been known as advanced and powerful tools to study tumor biological systems at the single-cell resolution and are playing increasingly critical roles in multiple stages of drug discovery and development. Specifically, single-cell technologies can promote the discovery of drug targets, help high-throughput screening at single-cell level, and contribute to pharmacokinetic studies of anti-tumor drugs. Emerging single-cell analysis technologies have been developed to further integrating multidimensional single-cell molecular features, expanding the scale of single-cell data, profiling phenotypic impact of genes in single cell, and providing full-length coverage single-cell sequencing. In this review, we systematically summarized the applications of single-cell technologies in various sections of drug discovery for tumor treatment, including target identification, high-throughput drug screening, and pharmacokinetic evaluation and highlighted emerging single-cell technologies in providing in-depth understanding of tumor biology. Single-cell-technology-based drug discovery is expected to further optimize therapeutic strategies and improve clinical outcomes of tumor patients.

Oncolytic viruses (OVs), a kind of emerging therapeutics for treating tumors, are characterized by high replication efficiency, superior killing effects, and few adverse reactions, which have shown great application prospects in preclinical tumor treatment trials. To overcome the limitations of OV monotherapy, recent studies have found that combination therapy with other anti-tumor therapeutics, especially with immunotherapy, yields promising outcomes in tumor eradication. Due to the advancements in genetic engineering, the combination of OVs with novel immunotherapy, including cellular immunotherapy, adoptive cellular immunotherapy, immune checkpoint inhibitors, cancer vaccines, cytokines, and bi- or tri-specific T cell engagers, has greatly improved clinical outcomes and quality of life of tumor patients. In this review, we systematically summarize the latest progress of OVs combined with immunotherapy in tumor treatment and highlight the future directions of the combination strategies, which will promote the clinical application of OVs in tumor therapy.