Ali Anvarian

Glioblastoma (GBM) is the most lethal primary brain tumor, with a median survival of 15 months despite intensive treatment. Chimeric antigen receptor (CAR) T-cell therapy, while transformative in hematological malignancies, consistently fails in GBM because the immunosuppressive tumor microenvironment (TME) drives T-cell exhaustion. We examined transcriptional programs, microenvironmental factors, and metabolic competition that collectively drive exhaustion in this context. Then we reviewed 5 convergent engineering strategies: localized cytokine delivery to bypass autocrine deficits; adjunctive antibody therapies to remodel the TME; oncolytic viruses armed with chemoattractants or cytokines as immunomodulators; coexpression of cytokine or chemokine receptors to provide survival signals; and multiplexed CRISPR-Cas9 editing to disrupt exhaustion checkpoints and enable site-specific CAR integration. Locoregional delivery consistently outperforms systemic administration, demonstrating that physical barriers are as critical as cellular engineering. Despite this progress, antigen heterogeneity, metabolic limitations, and the need for combinatorial targeting remain the principal unresolved challenges. An overview of the key concepts discussed in this review is presented in the graphical abstract.

Varicella-zoster virus (VZV) reactivation has been associated with impaired cell-mediated immunity and several systemic conditions; however, its relationship with thyroid hormone dysregulation remains poorly understood. This case report describes a herpes zoster-like eruption occurring in a patient with inadequately controlled Graves’ disease and discusses the possible biological mechanisms underlying this temporal association. A 33-year-old woman presented with unilateral erythematous, erosive, and crusted lesions involving the right maxillary division of the trigeminal nerve after developing clustered vesicles six days earlier. The patient had a one-year history of Graves’ disease and had discontinued antithyroid therapy two months before presentation. Physical examination revealed proptosis and diffuse bilateral goiter, while thyroid function testing demonstrated an elevated free thyroxine level of 2.13 ng/dL and a suppressed thyroidstimulating hormone level of <0.01 µIU/mL. A Tzanck smear showed multinucleated giant cells, supporting an alpha-herpesvirus infection, although VZV polymerase chain reaction testing was unavailable. Thyroid-stimulating hormone receptor antibody testing was also unavailable; therefore, Graves’ disease was diagnosed clinically based on the characteristic findings of hyperthyroidism, diffuse goiter, and proptosis. The patient was treated with acyclovir, thiamazole, propranolol, intravenous saline, and local wound care. Progressive clinical improvement was observed, characterized by reduced erythema, crust formation, and subsequent post-inflammatory hyperpigmentation. This case highlights a temporal association between poorly controlled Graves’ disease and a herpes zoster-like eruption. Nevertheless, the absence of virological confirmation and the inherent limitations of a single case preclude causal inference. The proposed involvement of thyroid hormone-mediated epigenetic and immune mechanisms should therefore be regarded as hypothesis-generating and requires validation in experimental and controlled clinical studies.