HLA-C and cancer: These alterations can lead to diminished responses to the potent anti-cancer activity of IFN-γ.91 Furthermore, genetic and epigenetic alterations that impair antigen presentation are also known to contribute to both primary and acquired resistance to ICIs, an effect observed irrespective of the TMB.92 This highlights the complexity of resistance mechanisms, suggesting that a high TMB alone is not sufficient to ensure responsiveness to ICIs, as cancer cells can evade the immune system by reducing MHC expression through a combination of genetic and epigenetic mechanisms.