The article "Primary, Adaptive and Acquired Resistance to Cancer Immunotherapy" by Sharma et al. discusses the mechanisms that limit the effectiveness of cancer immunotherapy and explores strategies to overcome these limitations. The authors highlight the dynamic nature of the immune system and cancer cells, emphasizing the continuous evolution of resistance mechanisms. They categorize resistance into primary, adaptive, and acquired resistance, detailing the molecular and cellular factors involved in each type. Primary resistance occurs when the tumor fails to recognize or respond to immunotherapy due to the absence of tumor antigens or the lack of MHC presentation. Adaptive resistance involves the tumor's ability to evade immune responses through mechanisms such as upregulation of immunosuppressive molecules like PD-L1 and TGFβ, and downregulation of interferon-gamma signaling. Acquired resistance arises after an initial response, often due to changes in T cell function, loss of antigen presentation, or the development of escape mutations in the cancer cells. The article also reviews the potential of combination therapies, such as combining CTLA-4 and PD-1/PD-L1 checkpoint inhibitors, to enhance efficacy and overcome resistance. It emphasizes the importance of monitoring resistance mechanisms through longitudinal tumor sampling and the development of predictive biomarkers. Finally, the authors discuss emerging strategies to enhance T cell function and convert "cold" tumors into "hot" tumors, including metabolic reprogramming and modulation of the gut microbiome.The article "Primary, Adaptive and Acquired Resistance to Cancer Immunotherapy" by Sharma et al. discusses the mechanisms that limit the effectiveness of cancer immunotherapy and explores strategies to overcome these limitations. The authors highlight the dynamic nature of the immune system and cancer cells, emphasizing the continuous evolution of resistance mechanisms. They categorize resistance into primary, adaptive, and acquired resistance, detailing the molecular and cellular factors involved in each type. Primary resistance occurs when the tumor fails to recognize or respond to immunotherapy due to the absence of tumor antigens or the lack of MHC presentation. Adaptive resistance involves the tumor's ability to evade immune responses through mechanisms such as upregulation of immunosuppressive molecules like PD-L1 and TGFβ, and downregulation of interferon-gamma signaling. Acquired resistance arises after an initial response, often due to changes in T cell function, loss of antigen presentation, or the development of escape mutations in the cancer cells. The article also reviews the potential of combination therapies, such as combining CTLA-4 and PD-1/PD-L1 checkpoint inhibitors, to enhance efficacy and overcome resistance. It emphasizes the importance of monitoring resistance mechanisms through longitudinal tumor sampling and the development of predictive biomarkers. Finally, the authors discuss emerging strategies to enhance T cell function and convert "cold" tumors into "hot" tumors, including metabolic reprogramming and modulation of the gut microbiome.