From molecular characteristics to clinical practice: current status and future prospects of immunotherapy for SMARCA4-deficient tumors.

Abstract

SMARCA4-deficient tumors arise from mutations, deletions, or fusions of the SMARCA4 gene that abrogate the function of its encoded protein BRG1. Defined by profoundly disrupted chromatin remodeling, these tumors carry a dismal prognosis, respond poorly to conventional therapies, and lack any standardized treatment approach. Accumulating clinical evidence indicates that a subset of patients derives meaningful and durable benefit from immune checkpoint inhibitor (ICI) therapy, representing a promising avenue for this rare and refractory disease. Here, we systematically review the clinicopathological features, tumor immune microenvironment (TIME), and co-mutational landscape of SMARCA4-deficient tumors, and examine how these factors influence immunotherapy outcomes, with a particular focus on ICI monotherapy and combination regimens. We further evaluate the potential of SMARCA4 deficiency as an independent predictive biomarker and outline future directions for advancing precision immunotherapy in this challenging disease context.