Cancer treatment faces significant challenges, particularly drug resistance, which is a major obstacle in effective therapy. Cancer cells develop resistance through various mechanisms, including genetic and epigenetic alterations, tumor heterogeneity, and interactions with the tumor microenvironment. These factors enable cancer cells to survive and progress under unfavorable conditions. Despite advances in targeted therapies, resistance remains a critical issue, necessitating the exploration of new therapeutic strategies such as combination therapy, precision immunotherapy, and stem cell-based approaches. Understanding the molecular mechanisms of resistance is crucial for developing more effective treatments. Tumor heterogeneity contributes significantly to drug resistance, as cancer cells exhibit diverse genetic and epigenetic changes that allow them to adapt to therapeutic pressures. Genetic and epigenetic alterations, such as DNA methylation and histone modifications, play a key role in drug resistance by affecting gene expression and cellular processes. Cancer stem cells (CSCs) are a major contributor to resistance and tumor relapse, as they possess self-renewal and differentiation capabilities. CSCs can evade chemotherapy by modulating drug efflux pumps, altering metabolic pathways, and interacting with the tumor microenvironment. The tumor microenvironment, including components like the extracellular matrix, cancer-associated fibroblasts, and immune cells, also influences drug resistance. Hypoxia, acidic environments, and immune suppression within the tumor microenvironment further enhance resistance. Additionally, the pH gradient across cellular organelles, such as lysosomes and mitochondria, plays a role in drug resistance by affecting drug transport and metabolic processes. Immune cells, particularly tumor-associated macrophages and regulatory T cells, contribute to drug resistance by promoting an immunosuppressive environment. The interplay between CSCs, the tumor microenvironment, and immune cells forms a complex network that supports resistance. Understanding these mechanisms is essential for developing novel therapeutic strategies to overcome drug resistance and improve cancer treatment outcomes.Cancer treatment faces significant challenges, particularly drug resistance, which is a major obstacle in effective therapy. Cancer cells develop resistance through various mechanisms, including genetic and epigenetic alterations, tumor heterogeneity, and interactions with the tumor microenvironment. These factors enable cancer cells to survive and progress under unfavorable conditions. Despite advances in targeted therapies, resistance remains a critical issue, necessitating the exploration of new therapeutic strategies such as combination therapy, precision immunotherapy, and stem cell-based approaches. Understanding the molecular mechanisms of resistance is crucial for developing more effective treatments. Tumor heterogeneity contributes significantly to drug resistance, as cancer cells exhibit diverse genetic and epigenetic changes that allow them to adapt to therapeutic pressures. Genetic and epigenetic alterations, such as DNA methylation and histone modifications, play a key role in drug resistance by affecting gene expression and cellular processes. Cancer stem cells (CSCs) are a major contributor to resistance and tumor relapse, as they possess self-renewal and differentiation capabilities. CSCs can evade chemotherapy by modulating drug efflux pumps, altering metabolic pathways, and interacting with the tumor microenvironment. The tumor microenvironment, including components like the extracellular matrix, cancer-associated fibroblasts, and immune cells, also influences drug resistance. Hypoxia, acidic environments, and immune suppression within the tumor microenvironment further enhance resistance. Additionally, the pH gradient across cellular organelles, such as lysosomes and mitochondria, plays a role in drug resistance by affecting drug transport and metabolic processes. Immune cells, particularly tumor-associated macrophages and regulatory T cells, contribute to drug resistance by promoting an immunosuppressive environment. The interplay between CSCs, the tumor microenvironment, and immune cells forms a complex network that supports resistance. Understanding these mechanisms is essential for developing novel therapeutic strategies to overcome drug resistance and improve cancer treatment outcomes.