Yuan Chen

The transcription factor homeodomain-only protein X (HOPX) is the smallest member of the homeodomain protein family. Lacking a DNA-binding domain, it acts as a co-effector, interacting with other transcription factors such as serum response factor (SRF) and GATA-binding factor 6 (GATA6) to regulate the differentiation and development of the heart and lung. HOPX exerts a tumor-suppressive function in various types of epithelial-derived carcinoma, while it promotes oncogenic effects in mesenchymal-derived sarcoma, indicating a distinct role of HOPX in the two major types of the malignancy. In addition, accumulating evidence shows that HOPX is expressed in the immune system and involved in the differentiation of immune cells. Recently, the emerging role of HOPX in metabolism has gained attention. This review describes the identification of HOPX in various tissues and discusses its role in carcinogenesis, as well as its functions in tissue differentiation, lipid metabolism, immunity, and the tumor microenvironment. The participation of HOPX in carcinogenesis and immunity implies that it may serve as a potential enhancer in tumor immunotherapy.

Adipose tissue dysfunction, which is associated with an increased risk of colorectal cancer (CRC), is a significant factor in the pathophysiology of obesity. Obesity-related inflammation and extracellular matrix (ECM) remodeling promote colorectal cancer metastasis (CRCM) by shaping the tumor microenvironment (TME). When CRC occurs, the metabolic symbiosis of tumor cells recruits adjacent adipocytes into the TME to supply energy. Meanwhile, abundant immune cells, from adipose tissue and blood, are recruited into the TME, which is stimulated by pro-inflammatory factors and triggers a chronic local pro-inflammatory TME. Dysregulated ECM proteins and cell surface adhesion molecules enhance ECM remodeling and further increase contractibility between tumor and stromal cells, which promotes epithelial-mesenchymal transition (EMT). EMT increases tumor migration and invasion into surrounding tissues or vessels and accelerates CRCM. Colorectal symbiotic microbiota also plays an important role in the promotion of CRCM. In this review, we provide adipose tissue and its contributions to CRC, with a special emphasis on the role of adipocytes, macrophages, neutrophils, T cells, ECM, and symbiotic gut microbiota in the progression of CRC and their contributions to the CRC microenvironment. We highlight the interactions between adipocytes and tumor cells, and potential therapeutic approaches to target these interactions.

HER2 (human epidermal growth factor receptor 2) is highly expressed in a variety of cancers, including breast, lung, gastric, and pancreatic cancers. Its amplification is linked to poor clinical outcomes. At the genetic level, HER2 is encoded by the ERBB2 gene (v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2), which is frequently mutated or amplified in cancers, thus spurring extensive research into HER2 modulation and inhibition as viable anti-cancer strategies. An impressive body of FDA-approved drugs, including anti-HER2 monoclonal antibodies (mAbs), antibody–drug conjugates (ADCs), and HER2-tyrosine kinase inhibitors (TKIs), have demonstrated success in enhancing overall survival (OS) and disease progression-free survival (PFS). Yet, drug resistance remains a persistent challenge and raises the risks of metastatic potential and tumor relapse. Research into alternative therapeutic options for HER2+ breast cancer therefore proves critical for adapting to this ever-evolving landscape. This review highlights current HER2-targeted therapies, discusses predictive biomarkers for drug resistance, and introduces promising emergent therapies—especially combination therapies—that are aimed at overcoming drug resistance in the context of HER2+ breast cancer.

Chimeric antigen receptor (CAR)-T cell immunotherapy represents a cutting-edge advancement in the landscape of cancer treatment. This innovative therapy has shown exceptional promise in targeting and eradicating malignant tumors, specifically leukemias and lymphomas. However, despite its groundbreaking successes, (CAR)-T cell therapy is not without its challenges. These challenges, particularly pronounced in the treatment of solid tumors, include but are not limited to, the selection of appropriate tumor antigens, managing therapy-related toxicity, overcoming T-cell exhaustion, and addressing the substantial financial costs associated with treatment. Nanomedicine, an interdisciplinary field that merges nanotechnology with medical science, offers novel strategies that could potentially address these limitations. Its application in cancer treatment has already led to significant advancements, including improved specificity in drug targeting, advancements in cancer diagnostics, enhanced imaging techniques, and strategies for long-term cancer prevention. The integration of nanomedicine with (CAR)-T cell therapy could revolutionize the treatment landscape by enhancing the delivery of genes in (CAR)-T cell engineering, reducing systemic toxicity, and alleviating the immunosuppressive effects within the tumor microenvironment. This review aims to explore how far (CAR)-T cell immunotherapy has come alone, and how nanomedicine could strengthen it into the future. Additionally, the review will examine strategies to limit the off-target effects and systemic toxicity associated with (CAR)-T cell therapy, potentially enhancing patient tolerance and treatment outcomes.

Abnormal expression of ACSL members 1, 3, 4, 5, and 6 is frequently seen in human cancer; however, their clinical relevance is unclear. In this study, we analyzed the expression of ACSLs and investigated the effects of the ACSL inhibitor Triacsin C (TC) in lung cancer. We found that, compared to normal human bronchial epithelial (NHBE) cells, ACSL1, ACSL4, and ACSL6 were highly expressed, while ACSL3 and ACSL5 were lost in the majority of lung cancer cell lines. ACSL activity was associated with the expression levels of the ACSLs. In primary lung tumors, a higher expression of ACSL1, ACSL4, and ACSL5 was significantly correlated with adenocarcinoma (ADC). Moreover, ACSL5 was significantly reversely related to the proliferation marker Ki67 in low-grade tumors, while ACSL3 was positively associated with Ki67 in high-grade tumors. Combination therapy with TC and Gemcitabine enhanced the growth-inhibitory effect in EGFR wild-type cells, while TC combined with EGFR-TKIs sensitized the EGFR-mutant cells to EGFR-TKI treatment. Taken together, the data suggest that ACSL1 may be a biomarker for lung ADC, and ACSL1, ACSL4, and ACSL5 may be involved in lung cancer differentiation, and TC, in combination with chemotherapy or EGFR-TKIs, may help patients overcome drug resistance.

The farnesoid-X receptor (FXR), a member of the nuclear hormone receptor superfamily, can be activated by bile acids (BAs). BAs binding to FXR activates BA signaling which is important for maintaining BA homeostasis. FXR is differentially expressed in human organs and exists in immune cells. The dysregulation of FXR is associated with a wide range of diseases including metabolic disorders, inflammatory diseases, immune disorders, and malignant neoplasm. Recent studies have demonstrated that FXR influences tumor cell progression and development through regulating oncogenic and tumor-suppressive pathways, and, moreover, it affects the tumor microenvironment (TME) by modulating TME components. These characteristics provide a new perspective on the FXR-targeted therapeutic strategy in cancer. In this review, we have summarized the recent research data on the functions of FXR in solid tumors and its influence on the TME, and discussed the mechanisms underlying the distinct function of FXR in various types of tumors. Additionally, the impacts on the TME by other BA receptors such as takeda G protein-coupled receptor 5 (TGR5), sphingosine-1-phosphate receptor 2 (S1PR2), and muscarinic receptors (CHRM2 and CHRM3), have been depicted. Finally, the effects of FXR agonists/antagonists in a combination therapy with PD1/PD-L1 immune checkpoint inhibitors and other anti-cancer drugs have been addressed.

Programmed death ligand 1 (PD-L1) strongly inhibits T cell activation, thereby aiding tumors in escaping the immune response. PD-L1 inhibitors have proven to be effective in the treatment of different types of cancer, including non-small cell lung cancer (NSCLC). Yet, the knowledge regarding the biological function of tumor-intrinsic PD-L1 in lung cancer remains obscure. In our study, we set the goal of determining the function of PD-L1 using overexpression and knockdown strategies. PD-L1 silencing resulted in decreased migratory and invasive ability of tumor cells, together with attenuated colony-forming capacity. Ectopic expression of PD-L1 showed the opposite effects, along with increased activities of MAPK and Wnt/β-catenin pathways, and the upregulation of Wnt/β-catenin target genes. Additionally, overexpression of PD-L1 was associated with dysregulated cellular and exosomal miRNAs involved in tumor progression and metastasis. In primary lung tumors, immunohistochemistry revealed that both PD1 and PD-L1 were highly expressed in squamous cell carcinoma (SCC) compared to adenocarcinoma (p = 0.045 and p = 0.036, respectively). In SCC, PD1 expression was significantly associated with tumor grading (p = 0.016). Taken together, our data suggest that PD-L1 may exert an oncogenic function in NSCLC through activating Wnt/β-catenin signaling, and may act as a potential diagnostic marker for lung SCC.

Exosomes represent extracellular vesicles of endocytic origin ranging from 30 to 100 nm that are released by most of eukaryotic cells and can be found in body fluids. These vesicles in carrying DNA, RNA, microRNA (miRNA), Long noncoding RNA, proteins, and lipids serve as intercellular communicators. Due to their role in crosstalk between tumor cells and mesenchymal stroma cells, they are vital for tumor growth, progression, and anticancer drug resistance. Lung cancer is a global leading cause of cancer‐related deaths with 5‐year survival rates of about 7% in patients with distant metastasis. Although the implementation of targeted therapy has improved the clinical outcome of nonsmall cell lung cancer, drug resistance remains a major obstacle. Lung tumor‐derived exosomes (TDEs) conveying molecular information from tumor cells to their neighbor cells or cells at distant sites of the body activate the tumor microenvironment (TME) and facilitate tumor metastasis. Exosomal miRNAs are also considered as noninvasive biomarkers for early diagnosis of lung cancer. This review summarizes the influence of lung TDEs on the TME and metastasis. Their involvement in targeted therapy resistance and potential clinical applications are discussed. Additionally, challenges encountered in the development of exosome‐based therapeutic strategies are addressed.

Fibulins (FBLNs), interacting with cell adhesion receptors and extracellular matrix (ECM) components, play multiple roles in ECM structures and tissue functions. Abnormal expression of FBLN2, one of the fibulin family members, contributes to tumor initiation and development. However, the function of FBLN2 in human non-small cell lung cancer (NSCLC) has not yet been elucidated. In this study, we found that FBLN2 was downregulated in 9 out of 11 lung cancer cell lines compared to normal bronchial epithelial cells, which was associated with DNA hypermethylation. Primary lung squamous cell carcinoma expressed significantly more FBLN2 protein compared to adenocarcinoma (p = 0.047). Ectopic expression of FBLN2 led to decreased cell proliferation, migration and invasion, accompanied by inactivated MAPK/ERK and AKT/mTOR pathways, while FBLN2 siRNA knockdown resulted in an opposite biological behaviour in NSCLC cells. Additionally, overexpression of FBLN2 led to dysregulation of cell adhesion molecules, ECM markers and a panel of lysate/exosome-derived-microRNAs, which are involved in cell adhesion and ECM remodelling. Taken together, our data indicate that FBLN2 is methylated and exerts a tumor suppressor function through modulation of MAPK/ERK and AKT pathways and regulation of cell adhesion and ECM genes. Moreover, FBLN2 might be a potential biomarker for the sub-classification of NSCLC.

Colorectal carcinoma (CRC) is one of the most frequently diagnosed carcinomas and one of the leading causes of cancer-related death worldwide. Metabolic reprogramming, a hallmark of cancer, is closely related to the initiation and progression of carcinomas, including CRC. Accumulating evidence shows that activation of oncogenic pathways and loss of tumor suppressor genes regulate the metabolic reprogramming that is mainly involved in glycolysis, glutaminolysis, one-carbon metabolism and lipid metabolism. The abnormal metabolic program provides tumor cells with abundant energy, nutrients and redox requirements to support their malignant growth and metastasis, which is accompanied by impaired metabolic flexibility in the tumor microenvironment (TME) and dysbiosis of the gut microbiota. The metabolic crosstalk between the tumor cells, the components of the TME and the intestinal microbiota further facilitates CRC cell proliferation, invasion and metastasis and leads to therapy resistance. Hence, to target the dysregulated tumor metabolism, the TME and the gut microbiota, novel preventive and therapeutic applications are required. In this review, the dysregulation of metabolic programs, molecular pathways, the TME and the intestinal microbiota in CRC is addressed. Possible therapeutic strategies, including metabolic inhibition and immune therapy in CRC, as well as modulation of the aberrant intestinal microbiota, are discussed.