The article reviews the molecular mechanisms of tumor-intrinsic resistance to immune checkpoint blockade (ICB) and explores strategies to overcome these mechanisms. Key factors contributing to resistance include insufficient tumor antigenicity, impaired interferon-γ (IFNγ) signaling, loss of major histocompatibility complex (MHC) class I expression, and dysregulation of oncogenic signaling pathways such as WNT-β-catenin, CDK4-CDK6, and MAPK. The role of tumor dedifferentiation and stemness in resistance is also discussed. Biomarkers of tumor-intrinsic resistance, such as de novo tumor-reactive T cells and PD-L1 expression, are reviewed. The article highlights the importance of pre-existing antitumoral immune responses and the potential of neoantigen-based therapies. Finally, it outlines approaches to overcome intrinsic resistance, including combination therapies with alternative immune checkpoints, enhancing antigen presentation, and targeting pattern recognition receptors.The article reviews the molecular mechanisms of tumor-intrinsic resistance to immune checkpoint blockade (ICB) and explores strategies to overcome these mechanisms. Key factors contributing to resistance include insufficient tumor antigenicity, impaired interferon-γ (IFNγ) signaling, loss of major histocompatibility complex (MHC) class I expression, and dysregulation of oncogenic signaling pathways such as WNT-β-catenin, CDK4-CDK6, and MAPK. The role of tumor dedifferentiation and stemness in resistance is also discussed. Biomarkers of tumor-intrinsic resistance, such as de novo tumor-reactive T cells and PD-L1 expression, are reviewed. The article highlights the importance of pre-existing antitumoral immune responses and the potential of neoantigen-based therapies. Finally, it outlines approaches to overcome intrinsic resistance, including combination therapies with alternative immune checkpoints, enhancing antigen presentation, and targeting pattern recognition receptors.