From Resistance to Vulnerability: Therapy-Induced Surface Receptor Plasticity in ALL as an Immunotherapeutic Opportunity

Acute lymphoblastic leukemia (ALL) is a genetically and epigenetically heterogeneous malignant disease characterized by different subtypes with varying sensitivities to conventional chemotherapy. Despite significant improvements in survival rates, relapse remains the primary cause of treatment failure, often associated with intrinsic or acquired drug resistance. First-line therapy at diagnosis represents a major determinant of relapse in ALL. In this study, we performed a transcriptome and drug response profiling analysis to identify subtype-specific cell surface proteins that are overexpressed in patients with poor response to induction therapy. We summarize the current state of knowledge regarding chemotherapy responses, resistance mechanisms to standard cytostatic drugs and the increasing importance of cell biomarkers as predictors of an adverse disease course and potential therapeutic targets. We discuss the results of clinical and molecular studies linking specific genomic alterations—such as KMT2A-rearrangements, Ph-like, DUX4-rearrangements and T-ALL—to drug resistance and highlight surface antigens like CSPG4, HER2, MCAM and ROR1 that define high-risk leukemia phenotypes. The integration of transcriptomic, immunophenotypic and drug response data could enable a new generation of risk-adapted, surface-directed strategies for relapse treatment in ALL. Our analysis therefore provides subtype-specific predictive therapeutic targets for relapse treatment in ALL.