Chemotherapy Resistance in Hematological Cancers: A Scoping Review of Molecular Pathways and Therapeutic Innovations

Chemotherapy continues to serve as a cornerstone of treatment for hematological malignancies. However, the emergence of resistance to chemotherapy significantly undermines its effectiveness and can adversely impact long-term patient survival. A comprehensive understanding of the multifactorial mechanisms driving resistance is imperative for enhancing outcomes. This scoping review synthesizes current evidence on the molecular pathways underpinning chemotherapy resistance in hematological cancers and highlights emerging therapeutic innovations aimed at overcoming these challenges. A systematic review of the extant literature was conducted, with a focus on the genetic, epigenetic, cellular, and microenvironmental mechanisms of resistance in leukemia, lymphoma, and multiple myeloma. The examination also encompassed recent advancements in targeted therapies, immunotherapies, epigenetic modulators, novel drug delivery systems, and personalized medicine. The phenomenon of resistance can be attributed to a multifaceted interplay of dynamic genetic mutations (e.g., TP53, FLT3-ITD), epigenetic dysregulation (e.g., DNA methylation, microRNA alterations), drug efflux mechanisms, cancer stem cell quiescence and metabolic reprogramming, enhanced DNA repair capacity, and tumor microenvironment-mediated protection. A range of novel therapeutic strategies have emerged, including FLT3, IDH, and BCL-2 inhibitors; CAR T-cell therapies; bispecific antibodies; and functional precision medicine approaches. These strategies hold great promise for addressing the challenges posed by drug resistance. However, they also face their own unique challenges related to resistance. Overcoming chemotherapy resistance in hematological malignancies necessitates a comprehensive, mechanism-driven approach that addresses the complex interplay of genetic, epigenetic, cellular, and microenvironmental factors. Future strategies should integrate multi-omics profiling, rationally designed combination therapies, targeted disruption of the tumor microenvironment, and adaptive precision medicine to achieve sustained remissions and improved long-term outcomes.