Abstract
<jats:p>This chapter provides a comprehensive analysis of the molecular determinants that govern both sensitivity and resistance to PD-1/PD-L1 immune checkpoint blockade. By delineating tumor-intrinsic mechanisms – such as genomic alterations, neoantigen burden, interferon pathway robustness, and oncogenic signaling – and integrating these with tumor-extrinsic influences, including immune microenvironment composition, stromal barriers, and host-microbiome interactions, the chapter offers a unified conceptual framework for understanding therapeutic heterogeneity. Additionally, it addresses the principal malignancies where immunotherapies are effective or not, as well as the respective biomarkers. This synthesis underscores the importance of predictive and prognostic biomarkers in refining patient selection, informing treatment strategies, and driving the development of next-generation precision immunotherapies.</jats:p>