No abstract

Esophageal cancer (EC) is frequently considered a lethal malignancy and is often identified at a later stage. It is one of the major causes of cancer-related deaths globally. The conventional treatment methods like chemotherapy, radiotherapy, and surgery offer limited efficacy and poor clinical outcome with a less than 25% 5-year survival rate. The poor prognosis of EC persists despite the growth in the development of diagnostic and therapeutic modalities to treat EC. This underlines the need to elucidate the complex molecular mechanisms that drive esophageal oncogenesis. Apart from the role of the tumor microenvironment and its structural and cellular components in tumorigenesis, mounting evidence points towards the involvement of the esophageal microbiome, inflammation, and their cross-talk in promoting esophageal cancer. The current review summarizes recent research that delineates the underlying molecular mechanisms by which the microbiota and inflammation promote the pathophysiology of esophageal cancer, thus unraveling targets for potential therapeutic intervention.

The DNA and protein complex known as chromatin is subject to post-translational modifications (PTMs), which regulate cellular functions, such that PTM dysregulation can lead to disease including cancer. One critical PTM is acetylation/deacetylation, which is being investigated as a means to develop targeted cancer therapies. The histone acetyl transferase (HAT) family of proteins perform histone acetylation. In humans, MOF (hMOF), a member of the MYST family of HATs, acetylate histone H4 at lysine 16 (H4K16ac). MOF-mediated acetylation plays a critical roles in the DNA damage response (DDR) and embryonic stem cell development. Functionally, MOF is found in two distinct complexes NSL in humans (Non Specific Lethal) and MSL (Male Specific Lethal) in flies. NSL complex is also being able to acetylate additional histone H4 sites. Dysregulation of MOF activity occurs in multiple cancers including ovarian, medulloblastoma, breast, colorectal and lung cancer. Bioinformatics analysis of KAT8, the gene encoding hMOF, indicated it is highly overexpressed in kidney tumors as part of a concerted gene co-expression program that would support high levels of chromosome segregation and cell proliferation. The linkage between MOF and tumor proliferation suggests there are additional functions of MOF that remain to be discovered.

Traditional cancer treatments use nonspecific drugs and monoclonal antibodies to target tumor cells. Chimeric antigen receptor (CAR)-T cell therapy, however, leverages the immune system's T-cells to recognize and attack tumor cells. T-cells are isolated from patients and modified to target tumor-associated antigens. CAR-T therapy has achieved FDA approval for treating blood cancers like B-cell acute lymphoblastic leukemia, large B-cell lymphoma, and multiple myeloma by targeting CD-19 and B-cell maturation antigens. Bi-specific chimeric antigen receptors may contribute to mitigating tumor antigen escape, but their efficacy could be limited in cases where certain tumor cells do not express the targeted antigens. Despite success in blood cancers, CAR-T technology faces challenges in solid tumors, including lack of reliable tumor-associated antigens, hypoxic cores, immunosuppressive tumor environments, enhanced reactive oxygen species, and decreased T-cell infiltration. To overcome these challenges, current research aims to identify reliable tumor-associated antigens and develop cost-effective, tumor microenvironment-specific CAR-T cells. This review covers the evolution of CAR-T therapy against various tumors, including hematological and solid tumors, highlights challenges faced by CAR-T cell therapy, and suggests strategies to overcome these obstacles, such as utilizing single-cell RNA sequencing and artificial intelligence to optimize clinical-grade CAR-T cells.

Protein ubiquitination is one of the most crucial posttranslational modifications responsible for regulating the stability and activity of proteins involved in homeostatic cellular function. Inconsistencies in the ubiquitination process may lead to tumorigenesis. Ubiquitin-specific peptidases are attractive therapeutic targets in different cancers and are being evaluated for clinical development. Ubiquitin-specific peptidase 37 (USP37) is one of the least studied members of the USP family. USP37 controls numerous aspects of oncogenesis, including stabilizing many different oncoproteins. Recent work highlights the role of USP37 in stimulating the epithelial-mesenchymal transition and metastasis in lung and breast cancer by stabilizing SNAI1 and stimulating the sonic hedgehog pathway, respectively. Several aspects of USP37 biology in cancer cells are yet unclear and are an active area of research. This review emphasizes the importance of USP37 in cancer and how identifying its molecular targets and signalling networks in various cancer types can help advance cancer therapeutics.