Background: Head and neck squamous cell carcinoma (HNSCC) is a malignant tumor of the oral mucosal epithelium. The high incidence of recurrence and metastasis presents substantial challenges for treatment, underscoring the complex molecular landscape underlying the disease. The purpose of this work is to clarify how HNSCC tumor cells and cancer-associated fibroblasts (CAFs) interact. Methods: Spatial transcriptome sequencing and single-cell RNA sequencing had been employed to describe the biological characteristics of CAFs in HNSCC. The biological connection between CAFs and tumor cells was verified by molecular interaction experiments. In addition, the regulatory effect of CAFs on oxidative stress in tumor cells and the phenotypic conversion of neutrophils were explored through a coculture system, a knockdown/overexpression method, flow cytometry, and animal experiments. Finally, potential small-molecule inhibitors were screened by molecular dynamics simulation and validated through in vitro and in vivo assays. Results: Growth differentiation factor 15 (GDF15) promoted tumor cell growth and invasion by enhancing PCNA clamp associated factor (PCLAF) transcription through interferon regulatory factor 5 modulation. Its interaction with the receptor GDNF family receptor alpha like (GFRAL) triggered chronic inflammatory signaling via the phosphatidylinositol-3 kinase/protein kinase b/signal transducer and activator of transcription 3 pathway, which led to oxidative stress imbalance and contributed to tumor progression and the development of drug resistance. Moreover, GDF15 activated the extracellular signal-regulated kinase 1/2 pathway through tumor necrosis factor-α, thereby facilitating neutrophil infiltration and promoting lung metastasis in HNSCC. Notably, risperidone (SM-2) emerged as a potential inhibitory regulator capable of disrupting the cascade effects mediated by the GDF15–GFRAL axis, underscoring its therapeutic relevance. Conclusion: This study identifies the GDF15–GFRAL signaling axis as a critical regulator of oxidative stress and immune evasion in HNSCC and demonstrates that the novel small-molecule SM-2 effectively targets this pathway, highlighting its potential as a promising therapeutic strategy.

Background: Globally, gastric cancer (GC) stands as the fifth most prevalent form of malignant neoplasm and represents a significant contributor to mortality associated with oncological conditions. Despite advancements in therapeutic strategies for GC, the outcomes for patients with advanced stages of the disease continue to be unfavorable, largely due to tumor heterogeneity and the challenges posed by resistance to therapeutic agents. Metabolic reprogramming is pivotal in driving the advancement of GC, contributing to the development of resistance to pharmacological treatments and facilitating the cancer’s ability to evade immune surveillance. Developing multi-target comprehensive treatment strategies by integrating tumor microenvironment (TME) modulation holds promise for significantly improving therapeutic efficacy.Methods: The study analyzed GC and identified key cell subtypes by integrating data derived from single-cell RNA-sequencing (scRNA-seq) alongside spatial transcriptomics information. Cell type identification was accomplished using the tool of Seurat, and the spatial distribution of cell types was revealed through the Robust Cell Type Decomposition technique. CellChat was used to analyze the interactions between key cell subtypes and other cells, and the “StLearn” package was employed to investigate spatial cell communication in depth. Additionally, the functional role of the key molecule ELK4 was validated through in vitro experiments.Results: This research utilized scRNA-seq combined with spatial transcriptomics to comprehensively analyze GC, identifying the C1 NDUFAB1+ subtype, which exhibited high proliferative activity, metabolic reprogramming capabilities, and immune evasion properties. It was found that the C1 NDUFAB1+ subtype closely interacted with fibroblasts and pericytes via the PARs signaling pathway. Additionally, in vitro experiments confirmed that knockdown of ELK4 substantially curbed tumor cell proliferation, migration, and invasion.Conclusion: This study revealed the main significance of the C1 NDUFAB1+ subtype in GC, elucidating its core mechanisms in tumor progression, metabolic reprogramming, and immune evasion. ELK4 was identified as a key regulatory factor that markedly enhanced the proliferation, migratory capacity, and invasive potential of tumor cells, while changes in the TME were a driving force behind immune suppression and drug resistance. The findings underscored the importance of developing specific therapeutic targets, targeting metabolic reprogramming, and overcoming immune evasion, providing new theoretical foundations.

Diabetic wound healing is a significant complication of diabetes mellitus, characterized by prolonged healing times, heightened infection risks, and potential amputations, necessitating innovative therapeutic approaches. This study aims to evaluate the efficacy of a novel injectable hydrogel, AP@HA-Si InjGel, which combines hyaluronic acid, silanol, and bioactive compounds to promote wound healing in diabetic patients. Utilizing a combination of in vitro assays, diabetic mouse models, and advanced techniques such as single-cell RNA sequencing, we demonstrated that AP@HA-Si InjGel significantly accelerates wound closure, enhances collagen deposition, and modulates macrophage polarization towards a pro-healing M2 phenotype while suppressing the inflammatory M1 phenotype. The hydrogel exhibited excellent biocompatibility with over 90 % cell viability and significant antioxidant properties, reducing reactive oxygen species accumulation. Histological analysis confirmed that AP@HA-Si InjGel promoted neovascularization and improved extracellular matrix remodeling, thereby enhancing tissue regeneration. Furthermore, single-cell RNA sequencing revealed distinct macrophage subtypes, with an increased proportion of M2 macrophages and a favorable differentiation trajectory towards enhanced wound healing. Overall, these findings highlight the therapeutic potential of AP@HA-Si InjGel as a comprehensive strategy for diabetic wound management, warranting further exploration in clinical settings to address the growing challenge of impaired wound healing in diabetic patients.