Abstract 4425: Quantum-inspired computing analysis of spatial omics uncovers immune pathways relevant to T-DXd resistance in metastatic breast cancer

Abstract Purpose: Trastuzumab deruxtecan (T-DXd) is a key therapy for HER2+/HER2-low metastatic breast cancer (mBC), but up to 50% of patients develop resistance. Resistance mechanisms have implicated dysfunctions in DNA repair, lysosomal activity, and immune responses. This study combines spatial omics and quantum-inspired regulatory network analysis to investigate tumor-immune-extracellular matrix interactions contributing to T-DXd resistance. Methods: Using NanoString GeoMX, spatial proteomics were analyzed in 29 metastatic tissue sections from 15 responsive (R) and 14 non-responsive (NR) patients. Across 6-8 regions of interest per section, immune and stromal components were quantified. Additionally, a subset of samples (n = 2R, 2NR) underwent GeoMX whole transcriptomics profiling and analysis using both classical and quantum-inspired algorithms. Results: NR tumors consistently exhibited immunosuppression, disorganized immune responses, upregulated fibronectin, and poor infiltration of granzyme B-producing cells. Organ-specific findings included:•NR bone and brain mets showed increased spatial correlations between dendritic cells and T-cell exhaustion markers (PD-L1, CTLA4), suggesting niches of immune suppression.•NR bone mets showed increased spatial correlation of fibronectin correlated with immune markers, indicating that stiffer ECM physically blocks immune infiltration. •R chest wall mets showed upregulated smooth muscle actin (SMA), possibly reflecting vascular remodeling and enhanced immune infiltration. Additionally, spatial transcriptomics analysis revealed the following::•Tumor-associated B cells were identified in NR samples, interacting with exhausted T cells and the Wnt-catenin pathway. •QuantumGRN revealed interactions in immune cells involving RBPP4 with DNMT3A and TAF4, linked to altered chromatin remodeling and transcription regulation, respectively. Conclusions: This work shows that T-DXd response is heavily influenced by microenvironment remodeling and immune infiltration. This work highlights the value of spatial omics for uncovering ADC-resistance mechanisms, as well as the value of quantum-inspired computing for identifying novel therapeutic targets. In addition to collecting more spatial and single-cell omics data, future directions include pathway validation in animal models and computationally simulating quantum and molecular dynamics of ADC resistance. Citation Format: Glori Das, Wenjuan Dong, Matthew Vasquez, Ji-hoon Lee, Yuan Gao, Jenny Chang, Xiaoxian Li, Hong Zhao, Stephen T. Wong. Quantum-inspired computing analysis of spatial omics uncovers immune pathways relevant to T-DXd resistance in metastatic breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4425.