T-cell activation requires antigen recognition (TCR-MHC) + co-stimulation (CD28-B7) but is balanced by inhibitory checkpoints — PD-1 (T-cell) engages PD-L1/PD-L2 (tumor or APC) → T-cell exhaustion. CTLA-4 outcompetes CD28 for B7 → blunts initial priming. Tumors hijack checkpoints to evade immunosurveillance. Checkpoint blockade releases the brake: anti-PD-1 (nivolumab, pembrolizumab) on T cells; anti-PD-L1 (atezolizumab, durvalumab) on tumors; anti-CTLA-4 (ipilimumab) priming-phase. Indications expanded to melanoma → NSCLC → renal → bladder → HCC → MSI-high tumors of any origin. Toxicity is autoimmune (irAEs): colitis, pneumonitis, hepatitis, endocrinopathies (thyroiditis → hypothyroidism, hypophysitis, T1DM, adrenal insufficiency) — managed by holding the drug ± systemic steroids.
Organ Systems
immune-hematologic
Pathway Steps
pd-1-pd-l1-binding → t-cell-exhaustion — via PD-1 phosphatase recruitment → TCR signal dampening. Tumor or tissue PD-L1 engaging PD-1 on T cells delivers an inhibitory signal that drives T-cell exhaustion — a brake tumors exploit to evade immunity. Blocking it (anti-PD-1 nivolumab/pembrolizumab; anti-PD-L1 atezolizumab) reinvigorates exhausted T cells, a transformative cancer immunotherapy.
ctla-4-b7-binding → t-cell-priming-suppression — via CTLA-4 outcompetes CD28 → reduced IL-2 + clonal expansion. CTLA-4 outcompetes the costimulatory receptor CD28 for B7 ligands on antigen-presenting cells, suppressing T-cell priming early in the lymph node. Blocking it (ipilimumab) lowers the activation threshold — the first checkpoint inhibitor proven to extend survival in melanoma.
Known Modulators
nivolumab (inhibitor) — PD-1 (on T cells). first PD-1 mAb approved (2014 melanoma); broad indications; irAE colitis + pneumonitis + endocrinopathies
pembrolizumab (inhibitor) — PD-1 (on T cells). PD-1 mAb; tissue-agnostic approval for MSI-H/dMMR tumors — first FDA biomarker-only indication
atezolizumab (inhibitor) — PD-L1 (on tumor + APC). PD-L1 mAb; NSCLC + bladder + TNBC; mechanism focuses on tumor-side ligand vs T-cell-side receptor