Extracellular vesicles (EVs) are lipid‐bilayer membrane structures secreted by most cell types. EVs act as messengers via the horizontal transfer of lipids, proteins, and nucleic acids, and influence various pathophysiological processes in both parent and recipient cells. Compared to EVs obtained from body fluids or cell culture supernatants, EVs isolated directly from tissues possess a number of advantages, including tissue specificity, accurate reflection of tissue microenvironment, etc., thus, attention should be paid to tissue‐derived EVs (Ti‐EVs). Ti‐EVs are present in the interstitium of tissues and play pivotal roles in intercellular communication. Moreover, Ti‐EVs provide an excellent snapshot of interactions among various cell types with a common histological background. Thus, Ti‐EVs may be used to gain insights into the development and progression of diseases. To date, extensive investigations have focused on the role of body fluid‐derived EVs or cell culture‐derived EVs; however, the number of studies on Ti‐EVs remains insufficient. Herein, we summarize the latest advances in Ti‐EVs for cancers and non‐cancer diseases. We propose the future application of Ti‐EVs in basic research and clinical practice. Workflows for Ti‐EV isolation and characterization between cancers and non‐cancer diseases are reviewed and compared. Moreover, we discuss current issues associated with Ti‐EVs and provide potential directions.

Anti-PD-1/PD-L1 immunotherapy has achieved impressive therapeutic outcomes in patients with multiple cancer types. However, the underlined molecular mechanism(s) for moderate response rate (15–25%) or resistance to PD-1/PD-L1 blockade remains not completely understood. Here, we report that inhibiting the deubiquitinase, USP8, significantly enhances the efficacy of anti-PD-1/PD-L1 immunotherapy through reshaping an inflamed tumor microenvironment (TME). Mechanistically, USP8 inhibition increases PD-L1 protein abundance through elevating the TRAF6-mediated K63-linked ubiquitination of PD-L1 to antagonize K48-linked ubiquitination and degradation of PD-L1. In addition, USP8 inhibition also triggers innate immune response and MHC-I expression largely through activating the NF-κB signaling. Based on these mechanisms, USP8 inhibitor combination with PD-1/PD-L1 blockade significantly activates the infiltrated CD8⁺T cells to suppress tumor growth and improves the survival benefit in several murine tumor models. Thus, our study reveals a potential combined therapeutic strategy to utilize a USP8 inhibitor and PD-1/PD-L1 blockade for enhancing anti-tumor efficacy.

Exosomes are membranous structures secreted by nearly all cell types. As critical messengers for intercellular communication, exosomes deliver bioactive cargoes to recipient cells and are involved in multiple physiopathological processes, including immunoregulation. Our pioneering study revealed that cancer cells release programmed death-ligand 1-positive exosomes into the circulation to counter antitumor immunity systemically via T cells. Tumor cell-derived exosomes (TDEs) also play an immunosuppressive role in other immunocytes, including dendritic cells (DCs), macrophages, natural killer (NK) cells, and myeloid-derived suppressor cells (MDSCs). Moreover, exosomes secreted by nontumor cells in the tumor microenvironments (TMEs) also exert immunosuppressive effects. This review systematically provides a summary of the immunosuppression induced by exosomes in tumor microenvironments, which modulates tumor growth, invasion, metastasis, and immunotherapeutic resistance. Additionally, therapeutic strategies targeting the molecular mechanism of exosome-mediated tumor development, which may help overcome several obstacles, such as immune tolerance in oncotherapy, are also discussed. Detailed knowledge of the specific functions of exosomes in antitumor immunity may contribute to the development of innovative treatments.

Many cancers including head and neck squamous cell carcinoma (HNSCC) are characterized by a metabolic rewiring with increased glucose uptake and lactate production, termed as aerobic glycolysis. Targeting aerobic glycolysis presents a promising strategy for cancer therapy. This study investigates the therapeutic potential of glycolysis blockage by targeting phosphofructokinase-2/fructose-2, 6-bisphosphatase 3 (PFKFB3) in HNSCC. 1-(4-pyridinyl)-3-(2-quinolinyl)-2-propen-1-one (PFK15) was used as a selective antagonist of PFKFB3. Glycolytic flux was determined by measuring glucose uptake, lactate production and ATP yield. PFKFB3 expression was examined using HNSCC tissue arrays. Cell proliferation, apoptosis and motility were analysed. HNSCC xenograft mouse model and metastasis mouse model were established to examine the therapeutic efficacy of PFK15 in vivo. HNSCC showed an increased PFKFB3 expression compared with adjacent mucosal tissues (P < 0.01). Targeting PFKFB3 via PFK15 significantly reduced the glucose uptake, lactate production and ATP generation in HNSCC cell lines. PFK15 suppressed cell proliferation, halted cell cycle progression and induced cell apoptosis. The invadopodia of HNSCC cells was markedly reduced after PFK15 treatment, thereby impairing cell motility and extracellular matrix degradation ability. The in vivo data from the xenograft mice models proved that PFK15 administration suppressed the tumor growth. And the results from the metastatic mice models showed administration of PFK15 alleviated the lung metastasis of HNSCC and extended the life expectancy of mice. The pharmacological inhibition of PFKFB3 via PFK15 suppressed tumor growth and alleviated metastasis in HNSCC, offering a promising strategy for cancer therapy.

Mounting evidence indicates that tumor-derived exosomes (TDEs) play critical roles in tumor development and progression by regulating components in the tumor microenvironment (TME) in an autocrine or paracrine manner. Moreover, due to their delivery of critical molecules that react to chemotherapy and immunotherapy, TDEs also contribute to tumor drug resistance and impede the effective response of antitumor immunotherapy, thereby leading to poor clinical outcomes. There is a pressing need for the inhibition or removal of TDEs to facilitate the treatment and prognosis of cancer patients. Here, in the present review, we systematically overviewed the current strategies for TDE inhibition and clearance, providing novel insights for future tumor interventions in translational medicine. Moreover, existing challenges and potential prospects for TDE-targeted cancer therapy are also discussed to bridge the gaps between progress and promising applications.