Long known as digestive organelles, lysosomes have now emerged as multifaceted centers responsible for degradation, nutrient sensing, and immunity. Growing evidence also implicates role of lysosome-related mechanisms in pathologic process. In this review, we discuss physiological function of lysosomes and, more importantly, how the homeostasis of lysosomes is disrupted in several diseases, including atherosclerosis, neurodegenerative diseases, autoimmune disorders, pancreatitis, lysosomal storage disorders, and malignant tumors. In atherosclerosis and Gaucher disease, dysfunction of lysosomes changes cytokine secretion from macrophages, partially through inflammasome activation. In neurodegenerative diseases, defect autophagy facilitates accumulation of toxic protein and dysfunctional organelles leading to neuron death. Lysosomal dysfunction has been demonstrated in pathology of pancreatitis. Abnormal autophagy activation or inhibition has been revealed in autoimmune disorders. In tumor microenvironment, malignant phenotypes, including tumorigenesis, growth regulation, invasion, drug resistance, and radiotherapy resistance, of tumor cells and behaviors of tumor-associated macrophages, fibroblasts, dendritic cells, and T cells are also mediated by lysosomes. Based on these findings, a series of therapeutic methods targeting lysosomal proteins and processes have been developed from bench to bedside. In a word, present researches corroborate lysosomes to be pivotal organelles for understanding pathology of atherosclerosis, neurodegenerative diseases, autoimmune disorders, pancreatitis, and lysosomal storage disorders, and malignant tumors and developing novel therapeutic strategies.

Mitochondria are generally considered essential for life in eukaryotic organisms because they produce most of the energy or adenosine triphosphate (ATP) needed by the cell. Beyond energy production, it is now widely accepted that mitochondria also play a pivotal role in maintaining cellular homeostasis and signaling. The two core processes of mitochondrial dynamics, fission and fusion, serve as crucial foundations for maintaining mitochondrial morphology, distribution, and quantity, thereby ensuring cellular homeostasis. Mitochondrial autophagy (mitophagy) ensures the selective degradation of damaged mitochondria, maintaining quality control. Mitochondrial transport and communication further enhance their role in cellular processes. In addition, mitochondria are susceptible to damage, resulting in dysfunction and disruption of intracellular homeostasis, which is closely associated with the development of numerous diseases. These include mitochondrial diseases, neurodegenerative diseases, cardiovascular diseases (CVDs) and stroke, metabolic disorders such as diabetes mellitus, cancer, infectious diseases, and the aging process. Given the central role of mitochondria in disease pathology, there is a growing need to understand their mechanisms and develop targeted therapies. This review aims to provide a comprehensive overview of mitochondrial structure and functions, with a particular focus on their roles in disease development and the current therapeutic strategies targeting mitochondria. These strategies include mitochondrial-targeted antioxidants, modulation of mitochondrial dynamics and quality control, mitochondrial genome editing and genetic therapy, and mitochondrial transplantation. We also discuss the challenges currently facing mitochondrial research and highlight potential future directions for development. By summarizing the latest advancements and addressing gaps in knowledge, this review seeks to guide future research and clinical efforts in the field of mitochondrial medicine.

Cancer continues to pose a major global health burden, with conventional therapeutic modalities such as surgical resection, chemotherapy, radiotherapy, and immunotherapy often hindered by limited tumor specificity, substantial systemic toxicity, and the emergence of multidrug resistance. The rapid advancement of nanotechnology has introduced functionalized nanomaterials as innovative tools in the realm of precision oncology. These nanoplatforms possess desirable physicochemical properties, including tunable particle size, favorable biocompatibility, and programmable surface chemistry, which collectively enable enhanced tumor targeting and reduced off-target effects. This review systematically examines recent developments in the application of nanomaterials for cancer therapy, with a focus on several representative nanocarrier systems. These include lipid-based formulations, synthetic polymeric nanoparticles, inorganic nanostructures composed of metallic or non-metallic elements, and carbon-based nanomaterials. In addition, the article outlines key strategies for functionalization, such as ligand-mediated targeting, stimulus-responsive drug release mechanisms, and biomimetic surface engineering to improve in vivo stability and immune evasion. These multifunctional nanocarriers have demonstrated significant potential across a range of therapeutic applications, including targeted drug delivery, photothermal therapy, photodynamic therapy, and cancer immunotherapy. When integrated into combinatorial treatment regimens, they have exhibited synergistic therapeutic effects, contributing to improved efficacy by overcoming tumor heterogeneity and resistance mechanisms. A growing body of preclinical evidence supports their ability to suppress tumor progression, minimize systemic toxicity, and enhance antitumor immune responses. This review further explores the design principles of multifunctional nanoplatforms and their comprehensive application in combination therapies, highlighting their preclinical efficacy. In addition, it critically examines major challenges impeding the clinical translation of nanomedicine. By identifying these obstacles, the review provides a valuable roadmap to guide future research and development. Overall, this work serves as an important reference for researchers, clinicians, and regulatory bodies aiming to advance the safe, effective, and personalized application of nanotechnology in cancer treatment.

Background: Metabolic reprogramming provides a new perspective for understanding cancer. The targeting of dysregulated metabolic pathways may help to reprogram the immune status of the tumor microenvironment (TME), thereby increasing the effectiveness of immune checkpoint therapy. Colorectal cancer (CRC), especially colon adenocarcinoma (COAD), is associated with poor patient survival. The aim of the present study was to identify novel pathways involved in the development and prognosis of COAD, and to explore whether these pathways could be used as targets to improve the efficacy of immunotherapy. Methods: Metabolism-related differentially expressed genes (MRDEGs) between tumor and normal tissues were identified using The Cancer Genome Atlas (TCGA) dataset, together with metabolism-related prognostic genes (MRPGs). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was performed separately for the MRDEGs and MRPGs. Gene Set Variation Analysis (GSVA) was also performed to explore the role of purine metabolism in COAD tumorigenesis. Consensus clustering of purine metabolism genes with the overall survival (OS) of patients and with anti-tumor immunity was also performed. Pearson correlation analysis was used to identify potential targets that correlated strongly with the expression of immune checkpoints. Results: A 6-gene signature that had independent prognostic significance for COAD was identified, together with a predictive model for risk stratification and prognosis. The most significantly enriched pathway amongst MRDEGs and MRPGs was purine metabolism. Differentially expressed purine metabolism genes could divide patients into two clusters with distinct prognosis and anti-tumor immunity. Further analysis suggested that purine metabolism was involved in anti-tumor immunity. Conclusions: This study confirmed the importance of metabolism-related pathways and in particular purine metabolism in the tumorigenesis, prognosis and anti-tumor immunity of COAD. We identified a 6-gene prognostic signature comprised of EPHX2, GPX3, PTGDS, NAT2, ACOX1 and CPT2. In addition, four potential immune-metabolic checkpoints (GUCY1A1, GUCY1B1, PDE1A and PDE5A) were identified, which could be used to improve the efficacy of immunotherapy in COAD.

Neoadjuvant immunochemotherapy (nICT) has emerged as a promising neoadjuvant strategy for esophageal squamous cell carcinoma (ESCC). Identification of the factors affecting responsiveness to nICT could help further improve treatment efficacy. In this study, we performed single-cell analysis on 14 patients with ESCC undergoing nICT and revealed tumor microenvironment (TME) features associated with differential treatment responses. Nonnegative matrix factorization (NMF) identified five coordinated cellular programs with distinct response associations. Specifically, the NMF3 program, mainly comprising immunosuppressive cell subsets, was enriched in the minimal or no pathologic tumor regression [tumor regression staging 3 (TRS3)] group, in which regulatory T cells (Treg) and dendritic cells (DC) exhibited a close correlation. In addition, elevated expression of mitochondrial transcription factor A (TFAM) in DCs was associated with increased Treg infiltration in the TRS3 group. A myeloid-specific Tfam knockout mouse model showed that TFAM deficiency reversed the immunosuppressive TME, inhibited tumor growth, and enhanced the response to anti–programmed cell death protein 1 therapy in ESCC. Mechanistically, TFAM deficiency in DCs activated the stimulator of IFN genes (STING)–TBK1–IRF3 pathway, thereby promoting DC maturation to enhance antitumor immunity. Overall, this study characterized the TME in residual ESCC after nICT and revealed an association between elevated TFAM expression in DCs and poor responsiveness to nICT. These findings indicate the critical role of TFAM deficiency in DCs in activating antitumor immunity, highlighting the potential of targeting TFAM to improve the efficacy of immunotherapy and optimize therapeutic strategies. Significance: TFAM mediates dendritic cell activation through the STING-TBK1-IRF3 pathway and is associated with responsiveness to neoadjuvant immunochemotherapy in esophageal squamous cell carcinoma, identifying TFAM as a putative immunotherapeutic target and biomarker.

Single-cell analysis of B cells, endothelial cells and fibroblasts.