All cells in the changing tumor microenvironment (TME) need a class of checkpoints to regulate the balance among exocytosis, endocytosis, recycling and degradation. The vesicular trafficking and secretion pathways regulated by the small Rab GTPases and their effectors convey cell growth and migration signals and function as meditators of intercellular communication and molecular transfer. Recent advances suggest that Rab proteins govern conventional and unconventional vesicular secretion pathways by trafficking widely diverse cargoes and substrates in remodeling TME. The mechanisms underlying the regulation of conventional and unconventional vesicular secretion pathways, their action modes and impacts on the cancer and stromal cells have been the focus of much attention for the past two decades. In this review, we discuss the current understanding of vesicular secretion pathways in TME. We begin with an overview of the structure, regulation, substrate recognition and subcellular localization of vesicular secretion pathways. We then systematically discuss how the three fundamental vesicular secretion processes respond to extracellular cues in TME. These processes are the conventional protein secretion via the endoplasmic reticulum-Golgi apparatus route and two types of unconventional protein secretion via extracellular vesicles and secretory autophagy. The latest advances and future directions in vesicular secretion-involved interplays between tumor cells, stromal cell and host immunity are also described.

Ubiquitination and deubiquitination are important forms of posttranslational modification that govern protein homeostasis. Deubiquitinating enzymes (DUBs), a protein superfamily consisting of more than 100 members, deconjugate ubiquitin chains from client proteins to regulate cellular homeostasis. However, the dysregulation of DUBs is reportedly associated with several diseases, including cancer. The tumor microenvironment (TME) is a highly complex entity comprising diverse noncancerous cells (e.g., immune cells and stromal cells) and the extracellular matrix (ECM). Since TME heterogeneity is closely related to tumorigenesis and immune evasion, targeting TME components has recently been considered an attractive therapeutic strategy for restoring antitumor immunity. Emerging studies have revealed the involvement of DUBs in immune modulation within the TME, including the regulation of immune checkpoints and immunocyte infiltration and function, which renders DUBs promising for potent cancer immunotherapy. Nevertheless, the roles of DUBs in the crosstalk between tumors and their surrounding components have not been comprehensively reviewed. In this review, we discuss the involvement of DUBs in the dynamic interplay between tumors, immune cells, and stromal cells and illustrate how dysregulated DUBs facilitate immune evasion and promote tumor progression. We also summarize potential small molecules that target DUBs to alleviate immunosuppression and suppress tumorigenesis. Finally, we discuss the prospects and challenges regarding the targeting of DUBs in cancer immunotherapeutics and several urgent problems that warrant further investigation.

Background: Esophageal squamous cell carcinoma (ESCC) is the sixth leading cause of cancer-associated death worldwide with a dismal overall 5-year survival rate of less than 20%. The standard first-line therapy for advanced ESCC is concomitant chemo-radiation therapy (CCRT); however, patients usually develop resistance, resulting in unfavorable outcomes. Therefore, it is urgent to identify the mechanisms underlying CCRT resistance and develop effective treatment strategies. Methods: Patients’ endoscopic biopsy tumor tissues obtained before CCRT treatment were used to perform RNA-seq and GSEA analysis. Immunohistochemical (IHC) staining, chromatin immunoprecipitation (ChIP), and promoter reporter analyses were conducted to investigate the relationship between SOX17 and NRF2. Xenograft mouse models were used to study the role of SOX17/NRF2 axis in tumor growth and the efficacy of carboxymethyl cellulose-coated zero-valent-iron (ZVI@CMC). Results: In this study, a notable gene expression signature associated with NRF2 activation was observed in the poor CCRT responders. Further, IHC staining of endoscopic biopsy of 164 ESCC patients revealed an inverse correlation between NRF2 and SOX17, a tumor-suppressive transcription factor with low expression in ESCC due to promoter hypermethylation. Using ChIP and promoter reporter analyses, we demonstrated that SOX17 was a novel upstream transcriptional suppressor of NRF2. In particular, SOX17^low/NRF2^high nuclear level significantly correlated with poor CCRT response and poor survival, indicating that the dysregulation of SOX17/NRF2 axis played a pivotal role in CCRT resistance and tumor progression. Notably, the in-house developed nanoparticle ZVI@CMC functioned as an inhibitor of DNA methyltransferases to restore expression of SOX17 that downregulated NRF2, thereby overcoming the resistance in ESCC. Additionally, the combination of ZVI@CMC with radiation treatment significantly augmented anticancer efficacy to inhibit tumor growth in CCRT resistant cancer. Conclusion: This study identifies a novel SOX17^low/NRF2^high signature in ESCC patients with poor prognosis, recognizes SOX17 as a transcriptional repressor of NRF2, and provides a promising strategy targeting SOX17/NRF2 axis to overcome resistance.

Background/Objectives: Influenza is a major global health challenge, causing thousands of deaths annually. Antiviral drugs, particularly oseltamivir, a neuraminidase inhibitor, have become essential therapeutic options due to their oral bioavailability and efficacy. Previous studies suggest a potential association between oseltamivir use and the onset of diabetes mellitus. However, further investigation is needed to establish a definitive link. Methods: This retrospective cohort study utilized data from the Taiwan National Health Insurance Research Database (NHIRD), including 1,631,968 patients (815,984 oseltamivir users) between 1 January 2009 and 28 December 2018. All statistical analyses were performed using SAS 9.4M8 software (SAS Institute Inc., Cary, NC, USA). Results: Cox proportional hazards regression and multivariate analyses revealed a statistically significant association between oseltamivir use and overall diabetes risk (HR = 1.027, p = 0.0186). While no significant association was observed for Type 1 diabetes (HR = 1.021; p = 0.06795), oseltamivir users showed a higher incidence of Type 2 diabetes (HR = 1.024; p < 0.05). Oseltamivir was also linked to increased risks of comorbidities, including dyslipidemia (HR = 1.295, p < 0.0001), chronic liver disease (HR = 1.446, p < 0.0001), hypertension (HR = 1.586, p < 0.0001), and obesity (HR = 2.949, p < 0.0001). Conclusions: Oseltamivir is associated with an increased risk of Type 2 diabetes but not Type 1, and related comorbidities.

Background/Objectives: Evidence has indicated an increased risk of stroke in individuals with influenza infection, and the administration of Oseltamivir revealed a lower stroke risk in these individuals. However, the impacts of Oseltamivir and stroke remain limited. Methods: The data used in this retrospective cohort study were extracted from the Taiwan National Health Insurance Research Database (NHIRD), which included 281,420 Oseltamivir users and 13,394,652 patients between 1 January 2009 and 31 December 2018. The Oseltamivir group was younger (age 40.1 ± 15.3 years) and had a lower prevalence of comorbidities compared to the non-user group (age 46.2 ± 16.0 years). Stroke incidence and mortality were compared using multivariable Cox proportional hazards models. Results: We compared the incidence of ischemic stroke among individuals without a history of ischemic stroke, stratified by Oseltamivir use. After adjusting for age, sex, and comorbidities, Oseltamivir use was not associated with a significantly different risk of stroke (adjusted HR = 1.02, 95% CI: 0.96–1.08; p = 0.511). The mortality among individuals with a history of ischemic stroke, being Oseltamivir users (n = 2502), exhibited a lower cumulative mortality rate compared to non-users (4.08% vs. 6.45%). The association remained significant after multivariable adjustment, with an adjusted hazard ratio for mortality of 0.74 (95% CI: 0.61–0.89; p = 0.002). Conclusions: In this large population-based cohort of patients without a history of ischemic stroke, Oseltamivir use during influenza infection was not associated with stroke incidence after adjusting for age, sex, and comorbidities. Notably, Oseltamivir use in patients with a history of ischemic stroke was associated with reduced all-cause mortality, suggesting a potential survival benefit that warrants further investigation.