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N6-methyladenosine (m 6 A) is a widely investigated RNA modification in studies on the “epigenetic regulation” of mRNAs that is ubiquitously present in eukaryotes. Abnormal changes in m 6 A levels are closely related to the regulation of RNA metabolism, heat shock stress, tumor occurrence, and development. m 6 A modifications are catalyzed by the m 6 A writer complex, which contains RNA methyltransferase-like 3 (METTL3), methyltransferase-like 14 (METTL14), Wilms tumor 1-associated protein (WTAP), and other proteins with methyltransferase (MTase) capability, such as RNA-binding motif protein 15 (RBM15), KIAA1429 and zinc finger CCCH-type containing 13 (ZC3H13). Although METTL3 is the main catalytic subunit, WTAP is a regulatory subunit whose function is to recruit the m 6 A methyltransferase complex to the target mRNA. Specifically, WTAP is required for the accumulation of METTL3 and METTL14 in nuclear speckles. In this paper, we briefly introduce the molecular mechanism of m 6 A modification. Then, we focus on WTAP, a component of the m 6 A methyltransferase complex, and introduce its structure, localization, and physiological functions. Finally, we describe its roles and mechanisms in cancer.

The DEAD-box helicase family member DDX3X (DBX, DDX3) functions in nearly all stages of RNA metabolism and participates in the progression of many diseases, including virus infection, inflammation, intellectual disabilities and cancer. Over two decades, many studies have gradually unveiled the role of DDX3X in tumorigenesis and tumour progression. In fact, DDX3X possesses numerous functions in cancer biology and is closely related to many well-known molecules. In this review, we describe the function of DDX3X in RNA metabolism, cellular stress response, innate immune response, metabolic stress response in pancreatic β cells and embryo development. Then, we focused on the role of DDX3X in cancer biology and systematically demonstrated its functions in various aspects of tumorigenesis and development. To provide a more intuitive understanding of the role of DDX3X in cancer, we summarized its functions and specific mechanisms in various types of cancer and presented its involvement in cancer-related signalling pathways.

Insufficient tumor accumulation and distribution of photosensitizers as well as low antitumor immunity severely restrict the therapeutic efficacy of photothermal therapy (PTT). Cancer-associated fibroblasts (CAFs) play a key role in tumor extracellular matrix (ECM) remodeling and immune evasion. Reshaping tumor microenvironment via CAF regulation might provide a potential approach for complete tumor elimination in combination with PTT. Here, tumor cell-derived microparticles co-delivering calcipotriol and Indocyanine green (Cal/ICG@MPs) are developed to modulate CAFs for improved PTT efficacy. Cal/ICG@MPs efficiently target tumor tissues and regulate CAFs to reduce tumor ECM, resulting in enhanced tumor accumulation and penetration of ICG to generate strong PTT efficacy and activate CD8 + T cell-mediated antitumor immunity. In addition, Cal/ICG@MPs-triggered CAF regulation enhances tumor infiltration of CD8 + T cells and ameliorates CAF-induced antigen-mediated activation-induced cell death of tumor-specific CD8 + T cells in response to PTT, eliciting long-term antitumor immune memory to inhibit tumor recurrence and metastasis. Our results support Cal/ICG@MPs as a promising drug to improve PTT efficacy in cancer treatment. Photothermal therapy (PTT) has emerged as a promising approach for cancer treatment. Here, in preclinical cancer models, the authors show that PTT efficacy could be improved using tumor cell-derived microparticles that co-deliver the photosensitizer indocyanine green and a vitamin-D receptor ligand, calcipotriol, resulting in tumor extracellular matrix remodelling and ameliorated anti-tumor immune responses.

The main challenges for programmed cell death 1(PD-1)/PD-1 ligand (PD-L1) checkpoint blockade lie in a lack of sufficient T cell infiltration, tumor immunosuppressive microenvironment, and the inadequate tumor accumulation and penetration of anti-PD-1/PD-L1 antibody. Resetting tumor-associated macrophages (TAMs) is a promising strategy to enhance T-cell antitumor immunity and ameliorate tumor immunosuppression. Here, mannose-modified macrophage-derived microparticles (Man-MPs) loading metformin (Met@Man-MPs) are developed to efficiently target to M2-like TAMs to repolarize into M1-like phenotype. Met@Man-MPs-reset TAMs remodel the tumor immune microenvironment by increasing the recruitment of CD8 + T cells into tumor tissues and decreasing immunosuppressive infiltration of myeloid-derived suppressor cells and regulatory T cells. More importantly, the collagen-degrading capacity of Man-MPs contributes to the infiltration of CD8 + T cells into tumor interiors and enhances tumor accumulation and penetration of anti-PD-1 antibody. These unique features of Met@Man-MPs contribute to boost anti-PD-1 antibody therapy, improving anticancer efficacy and long-term memory immunity after combination treatment. Our results support Met@Man-MPs as a potential drug to improve tumor resistance to anti-PD-1 therapy. Durable response rate to anti-PD-1/PD-L1 therapy remains relatively low in patients with cancer. Here the authors show that metformin-loaded mannose-modified macrophage-derived microparticles reprogram the tumor immune microenvironment and improve responses to anti-PD-1 therapy.

FAM134B (also called JK-1, RETREG1), a member of the family with sequence similarity 134, was originally discovered as an oncogene in esophageal squamous cell carcinoma. However, its most famous function is that of an ER-phagy-regulating receptor. Over the decades, the powerful biological functions of FAM134B were gradually revealed. Overwhelming evidence indicates that its dysfunction is related to pathophysiological processes such as neuropathy, viral replication, inflammation, and cancer. This review describes the biological functions of FAM134B, focusing on its role in ER-phagy. In addition, we summarize the diseases in which it is involved and review the underlying mechanisms.

The durable response rate to immune checkpoint blockade such as anti-programmed cell death-1 (PD-1) antibody remains relatively low in hepatocellular carcinoma (HCC), mainly depending on an immunosuppressive microenvironment with limited number of CD8 + T cells, especially stem-like CD8 + T cells, in tumor tissues. Here we develop engineered microparticles (MPs) derived from alpha-fetoprotein (AFP)-overexpressing macrophages to load resiquimod (R848@M2pep-MPs AFP ) for enhanced anti-PD-1 therapy in HCC. R848@M2pep-MPs AFP target and reprogram immunosuppressive M2-like tumor-associated macrophages (TAMs) into M1-like phenotype. Meanwhile, R848@M2pep-MPs AFP -reprogrammed TAMs act as antigen-presenting cells, not only presenting AFP antigen to activate CD8 + T cell-mediated antitumor immunity, but also providing an intra-tumoral niche to maintain and differentiate stem-like CD8 + T cells. Combination immunotherapy with anti-PD-1 antibody generates strong antitumor immune memory and induces abundant stem-like CD8 + T cell proliferation and differentiation to terminally exhausted CD8 + T cells for long-term immune surveillance in orthotopic and autochthonous HCC preclinical models in male mice. We also show that the R848-loaded engineered MPs derived from macrophages overexpressing a model antigen ovalbumin (OVA) can improve anti-PD-1 therapy in melanoma B16-OVA tumor-bearing mice. Our work presents a facile and generic strategy for personalized cancer immunotherapy to boost anti-PD-1 therapy. Tumor associated macrophages (TAMs) contribute to the immunosuppressive tumor microenvironment, including hepatocellular carcinoma (HCC). Here the authors show that macrophage-derived microparticles modified with a M2-like macrophage targeting peptide and loaded with the TLR7/8 agonist resiquimod reprogram TAMs from immunosuppressive to inflammatory, promoting anti-tumor immune responses in preclinical HCC models.

Mesenchymal stem cells (MSCs) have been reported to localize in colorectal carcinomas, and participate in the formation of the tumor microenvironment. They have recently been isolated from colorectal cancer tissues, and are implicated in the growth, invasion, and metastasis of cancer cells. However, the roles and detailed mechanisms associated with human colorectal cancer-derived MSCs (CC-MSCs) have not been fully addressed. In this study, we found that CC-MSCs increased the migration and invasion of colorectal cancer cells and promoted the tumorigenesis of colorectal cancer through epithelial-to-mesenchymal transition (EMT) in vitro. We also found that CC-MSCs enhanced the growth and metastasis of colorectal cancer in vivo. Mechanistically, we determined that interleukin-6 (IL-6) was the most highly expressed cytokine in the CC-MSC conditioned medium, and promoted the progression of colorectal cancer cells through IL-6/JAK2/STAT3 signaling, which activated PI3K/AKT signaling. We used anti-IL-6 antibody to target IL-6. Collectively, these results reveal that the IL-6 secreted by CC-MSCs enhances the progression of colorectal cancer cells through IL-6/JAK2/STAT3 signaling, and could provide a novel therapeutic or preventive target.

Integrinβ-1 (ITGB1) is a crucial member of the transmembrane glycoprotein signaling receptor family and is also central to the integrin family. It forms heterodimers with other ligands, participates in intracellular signaling and controls a variety of cellular processes, such as angiogenesis and the growth of neurons; because of its role in bidirectional signaling regulation both inside and outside the membrane, ITGB1 must interact with a multitude of substances, so a variety of interfering factors can affect ITGB1 and lead to changes in its function. Over the past 20 years, many studies have confirmed a clear causal relationship between ITGB1 dysregulation and cancer development and progression in a wide range of benign diseases and solid tumor types, which may imply that ITGB1 is a prognostic biomarker and a therapeutic target for cancer treatment that warrants further investigation. This review summarizes the biological roles of ITGB1 in benign diseases and cancers, and compiles the current status of ITGB1 function and therapy in various aspects of tumorigenesis and progression. Finally, future research directions and application prospects of ITGB1 are suggested. 9nmgxiQa1wzbE8JmMRRNVA Video Abstract

China has a high burden of hepatocellular carcinoma, and hepatitis B virus (HBV) infection is the main causative factor. Patients with hepatocellular carcinoma have a poor prognosis and a substantial unmet clinical need. The phase 2–3 ORIENT-32 study aimed to assess sintilimab (a PD-1 inhibitor) plus IBI305, a bevacizumab biosimilar, versus sorafenib as a first-line treatment for unresectable HBV-associated hepatocellular carcinoma. This randomised, open-label, phase 2–3 study was done at 50 clinical sites in China. Patients aged 18 years or older with histologically or cytologically diagnosed or clinically confirmed unresectable or metastatic hepatocellular carcinoma, no previous systemic treatment, and a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 were eligible for inclusion. In the phase 2 part of the study, patients received intravenous sintilimab (200 mg every 3 weeks) plus intravenous IBI305 (15 mg/kg every 3 weeks). In the phase 3 part, patients were randomly assigned (2:1) to receive either sintilimab plus IBI305 (sintilimab–bevacizumab biosimilar group) or sorafenib (400 mg orally twice daily; sorafenib group), until disease progression or unacceptable toxicity. Randomisation was done using permuted block randomisation, with a block size of six, via an interactive web response system, and stratified by macrovascular invasion or extrahepatic metastasis, baseline α-fetoprotein, and ECOG performance status. The primary endpoint of the phase 2 part of the study was safety, assessed in all patients who received at least one dose of study drug. The co-primary endpoints of the phase 3 part of the study were overall survival and independent radiological review committee (IRRC)-assessed progression-free survival according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT03794440. The study is closed to new participants and follow-up is ongoing for long-term outcomes. Between Feb 11, 2019 and Jan 15, 2020, we enrolled 595 patients: 24 were enrolled directly into the phase 2 safety run-in and 571 were randomly assigned to sintilimab–bevacizumab biosimilar (n=380) or sorafenib (n=191). In the phase 2 part of the trial, 24 patients received at least one dose of the study drug, with an objective response rate of 25·0% (95% CI 9·8–46·7). Based on the preliminary safety and activity data of the phase 2 part, in which grade 3 or worse treatment-related adverse events occurred in seven (29%) of 24 patients, the randomised phase 3 part was started. At data cutoff (Aug 15, 2020), the median follow-up was 10·0 months (IQR 8·5–11·7) in the sintilimab–bevacizumab biosimilar group and 10·0 months (8·4–11·7) in the sorafenib group. Patients in the sintilimab–bevacizumab biosimilar group had a significantly longer IRRC-assessed median progression-free survival (4·6 months [95% CI 4·1–5·7]) than did patients in the sorafenib group (2·8 months [2·7–3·2]; stratified hazard ratio [HR] 0·56, 95% CI 0·46–0·70; p<0·0001). In the first interim analysis of overall survival, sintilimab–bevacizumab biosimilar showed a significantly longer overall survival than did sorafenib (median not reached [95% CI not reached–not reached] vs 10·4 months [8·5–not reached]; HR 0·57, 95% CI 0·43–0·75; p<0·0001). The most common grade 3–4 treatment-emergent adverse events were hypertension (55 [14%] of 380 patients in the sintilimab–bevacizumab biosimilar group vs 11 [6%] of 185 patients in the sorafenib group) and palmar-plantar erythrodysaesthesia syndrome (none vs 22 [12%]). 123 (32%) patients in the sintilimab–bevacizumab biosimilar group and 36 (19%) patients in the sorafenib group had serious adverse events. Treatment-related adverse events that led to death occurred in six (2%) patients in the sintilimab–bevacizumab biosimilar group (one patient with abnormal liver function, one patient with both hepatic failure and gastrointestinal haemorrhage, one patient with interstitial lung disease, one patient with both hepatic faliure and hyperkalemia, one patient with upper gastrointestinal haemorrhage, and one patient with intestinal volvulus) and two (1%) patients in the sorafenib group (one patient with gastrointestinal haemorrhage and one patient with death of unknown cause). Sintilimab plus IBI305 showed a significant overall survival and progression-free survival benefit versus sorafenib in the first-line setting for Chinese patients with unresectable, HBV-associated hepatocellular carcinoma, with an acceptable safety profile. This combination regimen could provide a novel treatment option for such patients. Innovent Biologics. For the Chinese translation of the abstract see Supplementary Materials section.

Primary liver cancer (PLC) is the second leading cause of cancer mortality worldwide, and its morbidity unceasingly increases these years. Hepatitis B virus (HBV) infection accounted for approximately 50% of hepatocellular carcinoma (HCC) cases globally in 2015. Due to the lack of an effective model to study HBV-associated liver carcinogenesis, research has made slow progress. Organoid, an in vitro 3D model which maintains self-organization, has recently emerged as a powerful tool to investigate human diseases. In this review, we first summarize the categories and development of liver organoids. Then, we mainly focus on the functions of culture medium components and applications of organoids for HBV infection and HBV-associated liver cancer studies. Finally, we provide insights into a potential patient-derived organoid model from those infected with HBV based on our study, as well as the limitations and future applications of organoids in liver cancer research.