Background Antibody-mediated rejection (AMR) of liver allografts remains incompletely defined, particularly in biopsies classified as indeterminate for AMR under the current Banff criteria. Whether this category reflects the biological heterogeneity of antibody-mediated injury or is a distinct alloimmune phenotype remains unclear. Methods We performed Geo Mx spatially resolved transcriptomic profiling of six liver allograft biopsies from four patients representing definite AMR, AMR-indeterminate, a histology-negative, C4d-positive within-patient comparator, T-cell mediated rejection (TCMR), and a stable allograft control. All AMR-spectrum biopsies were from ABO-incompatible grafts. Immunofluorescence-guided segmentation identified 91 regions of interest (ROIs) across the CD68 + macrophage-enriched, hepatocyte, and pan-cytokeratin + epithelial compartments; CD45 + ROIs were recovered only from rejection biopsies (TCMR, n = 5; definite AMR, n = 1). After quality control, 90 ROIs and 12,466 genes were analyzed using compartment-stratified linear models with slide-level adjustments. Results Unsupervised analyses demonstrated that AMR-indeterminate biopsies clustered with definite AMR rather than TCMR, with shared upregulation of innate inflammatory and acute-phase transcripts (PLA2G2A, CRP, and SAA2) most prominent within macrophage-enriched and hepatocyte compartments. A direct comparison of AMR-indeterminate and definite AMR identified subtle distinctions, including IL-32 upregulation and non-significant enrichment of antigen presentation and NK cell–mediated cytotoxicity pathways (HLA-B, KIR3DL1). The TCMR reference biopsy showed upregulation of antigen processing and presentation pathways. Conclusions These pilot findings suggest that, in ABO-incompatible allografts, AMR-indeterminate biopsies may sit within the molecular spectrum of antibody-mediated injury rather than constitute a separate rejection entity. These findings are strictly hypothesis-generating; validation in HLA-DSA–driven, ABO-compatible AMR is a prerequisite for generalization.
Lung adenocarcinoma (LUAD), a major subtype of non-small cell lung cancer (NSCLC), remains a leading cause of cancer-related mortality despite major therapeutic advances. Precision oncology has revolutionized the management of LUAD by identifying actionable molecular biomarkers and developing targeted therapies. In this review, we summarize the major predictive biomarkers in LUAD, including EGFR, KRAS, ALK, ROS1, MET, RET, BRAF, HER2, NTRK, and PD-L1, and describe the currently approved targeted therapies and emerging therapeutic strategies. Recent advances in selective inhibitors, antibody-drug conjugates, and immune checkpoint inhibitors that have improved clinical outcomes in molecularly defined patient populations are highlighted. The review also discusses the molecular basis of acquired resistance, such as on-target mutations, bypass signalling activation, histological transformation, and epithelial-mesenchymal transition that continue to limit long-term therapeutic efficacy. We also discuss emerging strategies to overcome resistance, including combination therapies, next-generation inhibitors, liquid biopsy-guided monitoring, and artificial intelligence-assisted precision medicine. Collectively, these findings highlight the need for comprehensive molecular characterization and integrated biomarker-guided treatment strategies to improve therapeutic decision-making and clinical outcomes in LUAD.
