Mitochondrial Transfer–Related Immune‐Inflammatory States in Hepatocellular Carcinoma: Implications for Immunotherapy Response and Inflammatory Complication Assessment
Xiaofeng Zhang, Yuan Dong, Ya Xiao, Cong Li, Dong Wang, Jia Zou, Xun JiangBackground
Immune‐inflammatory heterogeneity complicates treatment selection in hepatocellular carcinoma (HCC), yet its relationship to intercellular mitochondrial transfer remains unclear. We investigated whether mitochondrial transfer–related expression patterns identify immune‐inflammatory states associated with prognosis and candidate treatment–response patterns.
Methods
We integrated transcriptomic data from TCGA‐LIHC, ICGC‐LIRI‐JP, GSE14520, GSE76427, and GSE149614. Nonnegative matrix factorization established the mitochondrial transfer–related subtype (MTS) classification, comprising MTS1 and MTS2; subtype assignments were projected to external cohorts using a nearest‐template prediction strategy. Multiomics and single‐cell analyses assessed prognosis, genomic instability, immune infiltration, T‐cell dysfunction and exclusion, cancer‐associated fibroblast states, intercellular communication, and predicted drug response. Sorafenib response, tumor‐cell SDC2 function, and acquisition of a stromal mitochondrial reporter were evaluated in HCC cell models.
Results
Two reproducible subtypes, MTS1 and MTS2, displayed distinct immune‐inflammatory and metabolic profiles. MTS2 showed metabolic reprogramming, inferred MMR/MSI‐related sample characteristics, increased mutation and neoantigen burdens, reduced T‐cell exclusion, and higher TIDE‐predicted immunotherapy response. Single‐cell‐derived signatures showed higher antigen‐presenting CAF (apCAF) scores in MTS2, despite a higher overall fibroblast proportion in MTS1. CellChat prioritized a candidate MDK–SDC2 interaction from hepatocyte‐annotated cells to CAFs. MTS2 also showed lower predicted Sorafenib IC50 values and greater Sorafenib sensitivity in vitro. Tumor‐cell SDC2 depletion enhanced Sorafenib‐induced apoptosis. MTS2‐like cells showed greater acquisition of mito‐RFP signal from LX‐2 cells; intact mitochondrial transfer, its functional consequences, and its dependence on MDK‐SDC2 signaling were not established.
Conclusion
The MTS classification identifies immune‐inflammatory states associated with recurrence outcomes and predicted treatment response in HCC; its utility for clinical treatment selection remains to be established. Prospective studies should determine whether this framework predicts immunotherapy benefit, treatment‐related inflammation, or inflammatory complications in clinical practice.