Cross-modal mapping of cancer stem-like cell plasticity using deep learning
Abstract Cancer stem-like cells (CSCs) play a pivotal role in driving tumor heterogeneity, therapeutic resistance, and disease progression. Despite the power of single-cell RNA sequencing (scRNA-seq) to resolve intratumoral hierarchies, there remains a need for robust, scalable tools to consistently profile CSCs across both single-cell and bulk transcriptomic data. To address this, we developed ACSCeND—a unified, machine learning–based framework that enables high-resolution CSC state classification and tissue-level deconvolution. ACSCeND comprises (i) a supervised classifier trained on curated scRNA-seq datasets to assign cells into pluripotent-like, multipotent-like, or unipotent-like states, and (ii) an attention-guided autoencoder that deconvolves CSC subtype proportions from bulk RNA sequencing data. Compared to existing tissue deconvolution tools, ACSCeND achieves superior performance, with higher accuracy across synthetic and real-world samples. Applied to over 25 000 tumor profiles from The Cancer Genome Atlas (TCGA), PREdiction of Clinical Outcomes from Genomics (PRECOG), tumor-relapse, and checkpoint inhibitor studies, ACSCeND reveals that CSC abundance strongly correlates with poor disease-free survival and reduced immunotherapy efficacy. Moreover, it uncovers distinct CSC-state-specific molecular programs, offering insights into CSC-driven heterogeneity and tumor evolution. The model also recapitulates known developmental hierarchies in noncancerous tissues, supporting its broader biological relevance. By integrating single-cell precision with bulk-level applicability, ACSCeND offers a robust, interpretable approach to profiling CSC dynamics and establishes CSC state as a clinically meaningful, pan-cancer biomarker for guiding stemness-informed therapies. ACSCeND is available as a python package (through pip) at https://pypi.org/project/ACSCeND/.