Science Journals — AAAS

BACKGROUND: Immunotherapies that target the interaction of programmed death 1 (PD-1) with its ligands, PD-L1 and PD-L2, have ushered in themodern oncology era. The PD-1 pathway is a key mediator of local immunosuppression in the tumormicroenvironment (TME) but can also modulate T cell priming against tumor antigens in secondary lymphoid tissues. In advanced inoperable cancers refractory to other treatments, drugs that block the PD-1 receptor on lymphocytes or the PD-L1 ligand on tumor and/or immune cells [anti–PD-(L)1] canmediate tumorregression.Althoughanti–PD-(L)1 treatment is broadly active and is regarded as a “common denominator” for cancer therapy, many tumors demonstrate de novo or acquired resistance. Using anti–PD-(L)1 therapies in the neoadjuvant (presurgical) setting,whenthe tumor is potentially “resectable for cure,” presents a potential solution. There is ample oncologic precedent for this approach with presurgical chemotherapies in breast and lung cancer, associating pathologic response with improved long-term clinical outcomes. OurReview focuses on the development of neoadjuvant immunotherapies in the era of PD-1 pathway blockade, highlighting particular considerations for immunological mechanisms, clinical development, and pathologic response assessments.