The Immune Checkpoint Inhibitors Journey: From Early Promise to Lasting Impact

Immune checkpoint inhibitors (ICIs) have transformed cancer therapy, yet their clinical impact is limited by immune-related adverse events (irAEs), therapeutic resistance, and the lack of reliable predictive biomarkers, contributing to a shift from early promise to a therapeutic plateau. irAEs affect multiple organ systems and may lead to treatment interruption and significant morbidity. Emerging strategies emphasize phenotype-driven and steroid-sparing approaches to control toxicity while preserving antitumor efficacy. Concurrently, primary and acquired resistance remain major challenges, driven by tumor-intrinsic mechanisms, immune microenvironment alterations, and host factors. Furthermore, current biomarkers, including programmed cell death ligand 1 (PD-L1) expression and tumor mutation burden, demonstrate inconsistent predictive performance across tumor types. Advances in immune profiling, genomics, and microbiome research are enabling more precise patient stratification and informing novel therapeutic strategies, including rational combinations and targeted immunomodulation. This position article synthesizes key barriers in ICI therapy while highlighting emerging opportunities to refine patient selection, improve safety, and enhance therapeutic durability. Together, these advances position the field to move beyond the current plateau toward a more precise, effective, and patient-centered era of immuno-oncology.