Natural Killer Cell-Based Immunotherapy in Retinoblastoma: Biological Basis, Preclinical Evidence, and Translational Challenges.

Authors

Abolfazl Parsi-Moud, Delbar Daneshjou, Parisa Shams, Marzieh Ebrahimi, Mohammad Faranoush

Published in

Pediatric blood & cancer. Nov 02, 2026. Epub Nov 02, 2026.

Abstract

Retinoblastoma (RB) is the most common primary intraocular malignancy of childhood. Although current multimodal treatment has considerably improved survival, advanced and recurrent disease still requires enucleation in a substantial proportion of cases and carries long-term psychosocial consequences. RB is driven primarily by biallelic inactivation of the RB1 tumor suppressor gene, together with secondary molecular and epigenetic alterations. A growing body of evidence indicates that RB tumors, particularly poorly differentiated and invasive forms, downregulate HLA Class I expression and antigen-processing machinery, a phenotype that favors escape from cytotoxic T-cell surveillance while creating a biological context that may favor natural killer (NK) cell-mediated recognition through missing-self mechanisms. Preclinical studies consistently show that NK and NK-like effector cells can lyse RB cell lines and enhance antibody-dependent cellular cytotoxicity when combined with anti-GD2 antibodies or chemotherapy, but clinical evidence remains extremely limited, with only a single heterogeneous pilot trial reported to date and no dedicated prospective studies in RB. This review critically synthesizes the biological rationale, preclinical evidence, and clinical/immunogenetic data for NK cell-based immunotherapy in RB and addresses the translational barriers unique to the intraocular environment, including uncertainties in immune cell trafficking across the blood-retinal barrier, delivery-route selection, and cell-manufacturing constraints. We conclude by proposing which RB subgroups, therapeutic platforms, and delivery strategies are most realistic for early clinical development, positioning NK cell-based therapy as a biologically rational adjunct rather than a replacement for current treatment.

PMID:
42969752
Bibliographic data and abstract were imported from PubMed on 02 Nov 2026.

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