Retinoblastoma and Its Tumor Microenvironment

Retinoblastoma is the most common intraocular malignancy of childhood and is most often driven by loss of the RB1 tumor suppressor gene. While current treatments achieve high survival rates, they are frequently associated with significant morbidity, highlighting the need for more precise, biology-driven therapeutic methods. Increasing evidence suggests that retinoblastoma progression is not dictated by neoplastic cells alone, but rather by complex interactions within the tumor microenvironment, including stromal and immune components. In this review, we examine the cellular and molecular landscape of retinoblastoma with a particular focus on the immune microenvironment, including the spatial distribution and functional roles of innate and adaptive immune cells, as well as immune checkpoint proteins such as PD-1, PD-L1, and CTLA-4. We discuss how tumor- and treatment-induced immune suppression shapes disease progression and therapeutic response, and how chemotherapy alters immune infiltration and checkpoint expression. Finally, we explore emerging immunotherapeutic and cell-based approaches, emphasizing the potential for combination therapies that integrate immune modulation to improve outcomes and reduce long-term toxicity in retinoblastoma.