Immune checkpoint inhibitors (ICIs) targeting CTLA-4 and the PD-1/PD-L1 axis have shown significant clinical benefits in various cancers, transforming oncology treatment. Unlike traditional therapies, ICIs enhance anti-tumor immunity by blocking co-inhibitory signals in T cells. While resistance is common with other therapies, some patients experience long-term responses, suggesting durable immune memory. However, initial responses are often binary, with many non-responders progressing rapidly. Late relapses are emerging, indicating acquired resistance. Understanding the mechanisms of innate and acquired resistance is crucial for improving ICI efficacy. Innate resistance involves tumor-intrinsic factors like genetic and epigenetic changes affecting neoantigen formation and presentation. Acquired resistance may result from tumor evolution, such as neoantigen loss or mutations in signaling pathways. Key mechanisms include insufficient T-cell generation, impaired T-cell function, and failure to form memory T cells. Tumor microenvironment factors, such as immune suppressive cells and cytokines, also contribute to resistance. Strategies to overcome resistance include enhancing antigen presentation, promoting immunogenic cell death, and modulating the tumor microenvironment. Epigenetic modifications and immune checkpoint inhibitors like PD-1 and CTLA-4 are being explored. Combination therapies with other immunotherapies or targeted agents are under investigation to improve outcomes. Future research aims to identify biomarkers and develop personalized approaches to optimize ICI use. Understanding these mechanisms is essential for improving patient responses and long-term survival.Immune checkpoint inhibitors (ICIs) targeting CTLA-4 and the PD-1/PD-L1 axis have shown significant clinical benefits in various cancers, transforming oncology treatment. Unlike traditional therapies, ICIs enhance anti-tumor immunity by blocking co-inhibitory signals in T cells. While resistance is common with other therapies, some patients experience long-term responses, suggesting durable immune memory. However, initial responses are often binary, with many non-responders progressing rapidly. Late relapses are emerging, indicating acquired resistance. Understanding the mechanisms of innate and acquired resistance is crucial for improving ICI efficacy. Innate resistance involves tumor-intrinsic factors like genetic and epigenetic changes affecting neoantigen formation and presentation. Acquired resistance may result from tumor evolution, such as neoantigen loss or mutations in signaling pathways. Key mechanisms include insufficient T-cell generation, impaired T-cell function, and failure to form memory T cells. Tumor microenvironment factors, such as immune suppressive cells and cytokines, also contribute to resistance. Strategies to overcome resistance include enhancing antigen presentation, promoting immunogenic cell death, and modulating the tumor microenvironment. Epigenetic modifications and immune checkpoint inhibitors like PD-1 and CTLA-4 are being explored. Combination therapies with other immunotherapies or targeted agents are under investigation to improve outcomes. Future research aims to identify biomarkers and develop personalized approaches to optimize ICI use. Understanding these mechanisms is essential for improving patient responses and long-term survival.