Tumor Microenvironment Remodeling Following Neoadjuvant Immunotherapy in Solid Tumors

Abstract

Neoadjuvant immune checkpoint blockade, delivered before rather than after surgical resection of a solid tumor, has moved in roughly a decade from a mechanistic hypothesis into a standard of care across non-small cell lung cancer, triple-negative breast cancer, urothelial carcinoma, and melanoma. This article synthesizes the clinical and mechanistic literature on how a short neoadjuvant course of checkpoint blockade remodels the tumor immune microenvironment, drawing on landmark randomized trials (CheckMate 816, KEYNOTE-671, KEYNOTE-522, NEOSTAR, ABACUS, and the OpACIN-neo/OpACIN program) that establish the magnitude of pathologic and survival benefit, together with the single-cell and spatial biology literature that has begun to resolve what that remodeling consists of at cellular resolution: reinvigoration and clonal expansion of pre-existing CD8 T cells, a shift in the effector-to-regulatory T cell balance, partial repolarization of tumor-associated macrophages, and a supportive role for tertiary lymphoid structures. We give particular weight to the paired pre- and post-treatment biopsy studies that this treatment sequence uniquely enables, while noting that the mechanistic literature remains concentrated in a small number of tumor types and modest cohort sizes relative to the large trial populations establishing clinical efficacy. Read together, the evidence supports neoadjuvant checkpoint blockade as a reproducible driver of favorable tumor immune microenvironment remodeling across multiple solid tumor types, while leaving predictive biomarker validation, myeloidand stroma-directed mechanistic detail, and generalization beyond lung cancer and melanoma as an open research agenda.