Chondrosarcoma (CS) is the second most common primary malignant bone tumor and comprises a heterogeneous group of cartilage-producing neoplasms with distinct histopathological, molecular, and clinical features. Surgery remains the cornerstone of treatment, whereas intrinsic resistance to conventional chemotherapy and radiotherapy limits therapeutic options for patients with unresectable or metastatic disease. This narrative review critically examines the molecular, genetic, epigenetic, metabolic, and microenvironmental mechanisms underlying CS development, progression, and treatment resistance and evaluates their translational implications. CS subtypes are associated with characteristic molecular alterations, including IDH1/2 mutations in central conventional CS, EXT1/2 disruption in secondary peripheral CS, and HEY1::NCOA2 fusion in mesenchymal CS. Additional alterations involving TP53, CDKN2A/RB1, and the TERT promoter contribute to disease progression. These events interact with dysregulated signaling pathways, metabolic and epigenetic reprogramming, hypoxia, extracellular-matrix remodeling, bone remodeling, and heterogeneous immune states. This biological complexity has prompted the investigation of mutant-IDH inhibitors, death receptor agonists, antiangiogenic and multitarget kinase inhibitors, immune-checkpoint blockade, and therapies targeting cell-cycle, epigenetic, metabolic, and microenvironmental dependencies. Nevertheless, most approaches have produced limited or predominantly cytostatic activity. Ozekibart has provided a positive randomized signal, with improved progression-free survival in conventional CS, whereas mutant-IDH1 inhibitors can achieve durable disease stabilization in selected patients but rarely induce objective responses. Future progress requires subtype-specific trials, assessment of pretreatment tumor growth kinetics, pharmacodynamic confirmation of target inhibition, and prospective integration of genomic, epigenetic, metabolic, and immune biomarkers.
Small interfering RNA (siRNA) has achieved clinical success in liver-directed therapies, but its translation to solid tumors remains limited by heterogeneous delivery and context-dependent target dependence. This review compares non-small cell lung cancer, pancreatic ductal adenocarcinoma, breast cancer, glioblastoma, and hepatocellular carcinoma across four interconnected dimensions: resistance networks, tumor microenvironmental reprogramming, metastatic progression, and delivery-system design. We examine how bypass signaling and phenotypic plasticity influence target selection, how stromal and immune compartments shape therapeutic responses, and how disease stage and organ-specific barriers alter delivery requirements. We then assess representative clinical RNA interference programs to distinguish evidence of tissue exposure and target engagement from antitumor activity and established clinical benefit. Across these settings, tumor accumulation does not establish productive cytosolic delivery, and target knockdown alone does not ensure durable disease control. We propose a context-dependent framework that aligns functional target dependence with the intended cell population, tissue environment, treatment timing, and delivery route. Priorities include resistance-informed combinations, prospective validation of delivery biomarkers, repeat-dose safety assessment, and carrier designs whose functional benefits justify their manufacturing complexity. By linking mechanistic comparison with clinical evidence, this review identifies testable criteria for selecting patients, evaluating functional delivery, and advancing siRNA therapeutics for solid tumors.
Currently, cancer treatment mainly includes surgery, radiotherapy, chemotherapy, immunotherapy, and targeted therapy, wherein radiotherapy is one of the core modalities. However, its efficacy is often limited by radiotherapy resistance in the tumour cells. In recent years, studies have found that tumour cells undergo lipid metabolic reprogramming to enhance lipid synthesis, uptake, and storage, thereby adapting to the energy and structural adjustment demands imposed by radiotherapy, gaining survival advantage and developing radiation resistance. This review mainly focused on the role of lipid metabolic changes, including fatty acids, cholesterol, and phospholipids, in radiation resistance, aiming to provide ideas for achieving individualised precision radiotherapy.
