Tumor Microenvironment and Immune Response Against Wilms Tumor: Evasion Mechanisms and Implications for Immunotherapeutic Approaches

Wilms tumor (WT) is the most common malignant renal tumor in childhood and represents one of the major success stories of pediatric oncology, with very good survival achieved through risk-adapted multimodal therapy. Nevertheless, a subset of patients-particularly those with diffuse anaplasia, blastemal-type tumors persisting after chemotherapy, or relapsed disease-continues to experience poor outcomes and significant long-term treatment-related morbidity. These challenges highlight the need for novel therapeutic strategies beyond conventional cytotoxic approaches. Growing evidence indicates that WT is characterized by a complex and distinctive tumor microenvironment (TME) shaped by its developmental origin and triphasic histology. Immune cell infiltration, inflammatory mediators, and immune checkpoint pathways interact differently with blastemal, epithelial, and stromal tumor components, generating heterogeneous immune surveillance and escape mechanisms. In particular, tumor-associated macrophages (TAMs), functionally impaired natural killer (NK) cells, and immunosuppressive stromal elements play a central role in shaping an immune milieu that may limit the efficacy of immune-based therapies. Although immunotherapy has changed the management of several adult malignancies and some pediatric cancers, its translation to WT has so far been limited, with modest results in unselected patient populations. Recent immunogenomic and proteogenomic studies, however, suggest the existence of biologically distinct WT subsets with different immune features and potential susceptibility to targeted immunotherapeutic approaches. This narrative review integrates pathological, immunological, and clinical perspectives to summarize current knowledge on the WT immune microenvironment, mechanisms of tumor immune evasion, and emerging immunotherapeutic strategies. By providing a unified framework, it aims at supporting a multidisciplinary approach for the rational development of future immune-based and combination therapies tailored to specific WT subgroups.