This review article explores tumor-intrinsic factors that lead to resistance against immune checkpoint blockade in cancer treatment. It highlights how the genetic, transcriptional, and functional profiles of tumor cells significantly influence the effectiveness of immunotherapies like those targeting CTLA4 or PD1–PD-L1. The authors discuss several molecular mechanisms of resistance, including insufficient tumor antigenicity, impaired interferon signaling pathways, loss of MHC molecule expression, and the impact of various oncogenic signaling pathways (such as WNT–β-catenin, CDK4–CDK6, MAPK, and PTEN loss). Finally, the article identifies biomarkers of tumor-intrinsic resistance and examines existing and emerging therapeutic strategies aimed at overcoming these challenges and improving patient outcomes.
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