Immunological Mechanisms and Outcomes of T-cell-Targeted Immunotherapy in Food Allergy: A Systematic Review.

Food allergy is an increasing public health concern characterized by inappropriate Th2-driven immune responses to otherwise harmless food antigens, leading to IgE-mediated hypersensitivity. Current management strategies rely on allergen avoidance and emergency interventions, which fail to address the root cause of immune dysregulation. Given the central role of helper T cells, particularly Th2 and regulatory T cells (Tregs), this systematic review evaluates the efficacy, safety, and immunological effects of three T cell-targeted allergen-specific immunotherapies: oral immunotherapy (OIT), sublingual immunotherapy (SLIT), and epicutaneous immunotherapy (EPIT). Thirteen studies, comprising 14 study arms, from four databases were included following PRISMA 2020 guidelines and PICOS-based selection. Based on the study design, RoB 2 and ROBINS-I tools were used to evaluate risk of bias. OIT demonstrated strong clinical and immunological outcomes, with high desensitization and sustained unresponsiveness (SU) rates, increased FOXP3⁺ Tregs, and suppression of Th2 cytokines (IL-4, IL-5, IL-13). SLIT showed moderate immunomodulatory effects with better tolerability, while EPIT provided the safest profile but limited T cell reprogramming. Overall, this review highlights the therapeutic potential of targeting T cells in food allergies and supports the use of OIT as the most effective current strategy, despite a higher risk of adverse events. While SLIT and EPIT remain promising, particularly in pediatric populations, further research is needed to enhance durability, personalize treatments, and combine immunotherapies with adjuncts such as biologics or Treg-promoting agents to achieve lasting immune tolerance. PROSPERO registration ID: CRD420251012358.