MicroRNAs and immunotherapy in testicular germ cell tumors: opportunities and challenges for modulation of the immune...

Testicular germ cell tumors (TGCTs) are the most common solid malignancies in young men and, despite high cure rates with cisplatin-based multimodal therapy, a clinically relevant subset of patients develops relapsed, platinum-refractory, or treatment-resistant disease with limited salvage options and substantial long-term morbidity. This unmet need has renewed interest in immunotherapy, yet the experience in TGCT has been notably less successful than in other malignancies. Although TGCTs often display PD-L1 expression, tumor-infiltrating lymphocytes, and other features suggestive of immune engagement, immune checkpoint inhibitors have produced largely disappointing results in unselected patients, underscoring the complexity of immune regulation in this immune-privileged disease. Recent conceptual advances place microRNAs (miRNAs) at the center of this problem. Beyond their established diagnostic and prognostic value, miRNAs are increasingly recognized as upstream regulators of immune checkpoints, antigen-presentation pathways, cytokine signaling, macrophage polarization, dendritic-cell and T-cell function, and extracellular-vesicle-mediated tumor-immune crosstalk. This positions miRNAs not only as biomarkers of disease activity, but also as plausible determinants of immunotherapy sensitivity or resistance. At the same time, the field remains marked by important controversies: PD-L1 expression alone is an unreliable predictor of response; the relative contribution of low tumor mutational burden, testicular immune privilege, and microenvironmental suppression remains unresolved; and many proposed TGCT-associated miRNAs with an immunoregulatory role are still inferential rather than causally validated in disease-specific models. Accordingly, major gaps persist in defining which miRNAs are true functional drivers of immune escape in seminomatous versus non-seminomatous TGCT, how they interact with therapy-induced tumor evolution, and which delivery platforms can achieve safe, tumor-directed modulation. We argue that the next phase of the field should move beyond descriptive biomarker studies toward mechanism-based, TGCT-specific translational strategies integrating miRNA mimics, antagomirs, extracellular vesicles, or miRNA-augmented cellular therapies with immune-priming approaches such as epigenetic therapy, radiotherapy, vaccines, or CAR-T platforms. Such a framework could enable more precise biological stratification and improve the efficacy, durability, and tolerability of immunotherapy in refractory TGCT.