Biochimica et biophysica acta. Reviews on cancer最新文献

The onset and progression of pancreatic ductal adenocarcinoma (PDAC) influence acinar cells, leading to metaplastic and neoplastic adaptations. Lineage tracing experiments demonstrate the inherent plasticity of pancreatic acinar cells towards various subtypes, including tuft cells (TCs), enteroendocrine cells (EECs), gastric pit-like cells, and senescent cells. These cell types contribute to the injury resolution and maintenance of tissue homeostasis. Further transition of certain acinar subtypes, such as TCs, into metaplastic neuroendocrine cells and neural-like progenitors results in an aggressive PDAC phenotype and poor prognosis. This review describes the factors driving the specification trajectory of pancreatic acinar cell subtypes, their metabolic and functional preferences, particularly in the context of tumor microenvironment (TME) modulation, and their utility as an attractive target for improved survival outcomes. We emphasize the roles of TME components, including cancer-associated fibroblasts, immune cells, oncomucins, and various signaling mediators, in acinar subtype specification. The review highlights the concept of acinar metaplastic duct heterogeneity and its implications for targeting aggressive acinar subtypes to improve survival outcomes.

Bone is a highly dynamic tissue undergoing continuous remodelling through the coordinated actions of osteocytes, osteoblasts and osteoclasts. This process is tightly regulated by key signalling pathways, including the RANK/RANKL/Osteoprotegerin system, which governs bone resorption and formation. In addition, the CXCL12/CXCR4 axis and G-protein-coupled receptor 4 (GPCR4) play crucial roles in bone development, remodelling, and pathological conditions such as cancer progression. Skeletal metastases arise from complex interactions between tumour cells and the bone microenvironment, facilitating arrest, extravasation, and colonisation at secondary sites. In osteosarcoma and metastatic cancers, these molecular mechanisms contribute to tumour growth, bone degradation, bone formation and disease progression. This review highlights the intricate crosstalk between bone remodelling pathways and tumour cell invasion, providing insights into potential therapeutic targets for osteosarcoma and bone metastases.

Trastuzumab deruxtecan (T-DXd) has emerged as a revolutionary antibody-drug conjugate (ADC) that has shown remarkable clinical efficacy across multiple HER2-expressing tumor types. Comprising a humanized anti-HER2 monoclonal antibody linked to a potent topoisomerase I inhibitor via a cleavable and stable tetrapeptide-based linker, T-DXd integrates the specificity of targeted therapy with the cytotoxic potency of chemotherapy. As the most promising ADC in the era of precision oncology, T-DXd has been approved to treat a series of malignant tumors. However, its widespread clinical application is challenged by treatment-related adverse events, the emergence of drug resistance, and uncertainties in biomarker-guided patient selection. This review provides a comprehensive overview of T-DXd's molecular design, mechanisms of action, and major findings from key clinical trials. It also examines resistance pathways and safety considerations, and discusses strategies to optimize therapeutic outcomes, including rational combination approaches with immune checkpoint inhibitors or other targeted agents. Finally, we explore future directions in T-DXd development, emphasizing the importance of precision medicine, biomarker refinement, and next-generation ADC engineering to further enhance efficacy and safety.

Cutaneous melanoma is the most aggressive form of skin cancer characterized by high metastatic potential and poor prognosis, particularly in advanced stages (stage III/IV). Despite more than a decade of significant advances in treatment including immunotherapies, oncolytic virus therapy, and adoptive cell therapy, clinical outcomes for patients with advanced melanoma remain unsatisfactory. This is primarily due to the tumor's intrinsic aggressiveness, intolerable side effects associated with treatments, and the rapid emergence of therapeutic resistance. Therefore, there is a critical need for novel therapeutic strategies that not only inhibit melanoma progression and metastasis but also overcome resistance mechanisms. After reviewing recent therapeutic developments, we highlight the potential of store-operated Ca²⁺ entry (SOCE) as a promising and thus far overlooked target to improve the efficacy of current melanoma therapies. We examine the role of SOCE in oncogenic signaling pathways driving melanoma progression and invasiveness. Emphasis is given to the key mechanisms regulated by SOCE that underlie therapeutic resistance. We further discuss how modulation of SOCE has the potential to reshape a tumor response to therapy by disrupting these mechanisms. Integrating SOCE modulation in combination with existing treatment paradigms holds significant potential for advancing more precise, durable, and patient-tailored interventions in advanced melanoma.

The incidence of cancer in humans has been rising in association with extended life spans. Incidence rates of early onset cancers in humans <55 years of age have also been increasing for unclear reasons. One potential contributory factor is an antagonistic pleiotropy in which certain genes that appeared in mammals to increase fitness for reproduction contribute to cancer susceptibility later in life. A related concept is an evolutionary mismatch in which humans have adapted to certain environmental and dietary factors that change over time and thereby increase cancer incidence. The MUCIN 1 (MUC1) gene emerged in mammals and represents an example of antagonistic pleiotropy and evolutionary mismatch that is posited here as a contributing factor to the increasing incidence of cancer in humans. This Review focuses on the roles of MUC1 and the oncogenic M1C protein in reproductive fitness and barrier tissue protection that in settings of chronic inflammation promote pan-cancer progression and treatment resistance. Also highlighted are therapeutic approaches targeting MUC1 and M1C that are under clinical and pre-clinical development.

Colorectal cancer (CRC) represents a formidable global health challenge, with over 1.14 million new cases and 538,000 deaths estimated in 2022. The multifactorial nature of CRC carcinogenesis limits conventional therapies, thus demanding innovative treatment approaches. Metallodrugs have emerged as promising anticancer agents due to their unique physicochemical properties and unique mechanisms of action. However, their clinical translation is hindered by poor aqueous solubility, limited stability, and significant systemic toxicity. This comprehensive review examines the integration of organic nanoparticles and biomimetic smart nanocarriers to overcome metallodrug limitations in CRC therapy. We systematically analyse three major nanocarrier classes: lipid-based systems, protein-based platforms, and polymeric carriers. Critical evaluation criteria encompass synthesis complexity, scalability, biocompatibility, and translational feasibility. Each nanocarrier offers exclusive advantages: liposomes provide clinical maturity, protein nanoparticles present exceptional biocompatibility, and polymeric systems enable superior customization. Current preclinical successes demonstrate remarkable therapeutic improvements, with several candidates advancing to clinical evaluation. Although widespread impact is expected to happen gradually, ongoing developments continue to show promise. Advances in manufacturing scalability and long-term safety will be some critical points for the progress of these nanotherapeutic strategies for CRC management.

Immunotherapy, by activating the patient's immune system to eliminate tumors, has become a revolutionary strategy in cancer treatment. Among immunotherapy, immune checkpoint blockade (ICB) and adoptive cell therapy (ACT) have demonstrated significant efficacy in various solid tumors and hematological malignancies. However, problems such as insufficient clinical response rate, acquired drug resistance, and immune-related adverse reactions have limited its wide application, which is closely related to the immunosuppressive network formed by the dynamic evolution of the tumor microenvironment (TME) during the treatment process. TME is not only a "sanctuary" for tumors, but also a core hub for regulating the function of immune cells. Recent studies have shown that the dynamic changes of TME have spatiotemporal heterogeneity in immunotherapy and generate favorable or unfavorable mechanisms during the process of tumor immunotherapy, thereby affecting the efficacy of immunotherapy. This review systematically integrates the dynamic trajectories of TME revealed by cutting-edge technologies such as scRNA-seq and spatial transcriptomics. It analyzes the spatiotemporal evolution laws of immune cell subsets under ICB treatment. This article aims to elaborate on the dynamic trajectory and phenotypic changes of the TME during the immunotherapy treatment, providing meaningful insights into cancer immunotherapy.

SAG (Sensitive to Apoptosis Gene), also known as RBX2/ROC2/RNF7, was originally cloned as a redox-inducible gene encoding a cysteine-enriched antioxidant protein. SAG was subsequently characterized as the second family member of the RBX with RING domain, essential for E3 ligase activity in both ubiquitylation and neddylation. Data accumulated over the past 26 years have shown that SAG is overexpressed in many types of human cancer tissues with positive correlation of poor patient survival. Functional studies have revealed that SAG is essential for cancer cell growth, and for tumorigenesis induced by oncogene activation and tumor suppressor inactivation in several genetically modified mouse models. Mechanistically, SAG acts as a catalytic subunit of CRL5 as well as CRL1 to ubiquitylate and degrade mainly tumor suppressor substrates, whereas SAG knockdown or knockout causes their accumulation to inhibit the growth and survival of cancer cells, and tumor progression. Thus, SAG E3 is emerging as an attractive anti-cancer target with drug discovery of small molecule inhibitors and PROTAC degraders being currently pursued. Here, we provide a comprehensive literature review on SAG, from its molecular cloning, biochemical activities, and biological function, to SAG validation as an anti-cancer target, and finally to the drug discovery efforts of SAG targeting agents. The perspectives are also proposed for current challenges and future directions on the study of SAG-associated neddylation-CRLs.

Chordoma is a rare, malignant bone tumor characterized by high local recurrence rates and resistance to conventional therapies. While immunotherapy has emerged as a promising avenue, its clinical efficacy is currently limited by a profoundly immunosuppressive tumor immune microenvironment (TIME). This review systematically elucidates the molecular and cellular mechanisms underpinning the distinct "immune-excluded" phenotype in chordoma. In this architecture, effector T cells are physically sequestered from tumor cells by dense stromal septa, which paradoxically function as hubs for myeloid-T cell interaction rather than simple physical barriers. This immune-excluded architecture is orchestrated through multiple interconnected mechanisms. Cancer-associated fibroblasts (CAFs), particularly inflammatory and stress-related subpopulations, construct physical barriers via extracellular matrix remodeling while secreting chemokines (such as CXCL12) that spatially anchor T cells within the stroma. The transforming growth factor-beta (TGF-β) pathway reinforces this exclusion by suppressing cytotoxic T cell function and impeding tumor infiltration. Intrinsically, chordoma exhibits a low tumor mutational burden and specific genomic alterations-most notably the loss of CDKN2A/B and PBRM1. Furthermore, despite high chromosomal instability (CIN), co-occurring deletions of 9p and 10q silence the cGAS-STING pathway, thereby impairing antigen presentation and immune cell recruitment. The microenvironment is further dominated by M2-polarized tumor-associated macrophages and regulatory T cells, driving effector T cell exhaustion. Clinical evidence indicates that immune checkpoint inhibitors and targeted vaccines yield limited efficacy as monotherapies, highlighting the immune-excluded phenotype and the scarcity of PD-L1 protein expression as primary obstacles. Future therapeutic breakthroughs will require rational combination strategies, including CAR-T cell therapies targeting novel antigens (e.g., B7-H3) and adoptive T-cell transfer, designed to dismantle stromal barriers and exploit systemic anti-tumor immunity.

Tissue factor (TF) serves as a pivotal initiator of coagulation and has been extensively acknowledged for its substantial involvement in cancer progression and metastasis. Recent evidence suggests that targeting TF can enhance the infiltration of immune effector cells, thereby reshape the tumor microenvironment (TME). Despite these advancements, a comprehensive review of TF's role within the TME has yet to be conducted. This review uniquely synthesizes emerging evidence on TF-mediated immunosuppression mechanisms and evaluates cutting-edge targeting strategies to overcome therapy resistance.