T-Cell Synaptosomes Orchestrate Long-Term Anti-Tumor Immunity via Proliferative and Metabolic Reprogramming

Abstract

A defining feature of T-cell activation is its dependence on physical contact with antigen-presenting cells (APCs). During this interaction, activated T cells release microvesicles, known as T-cell immunological synaptosomes (TIS), onto the surface of APCs. While TIS are known to activate APCs, their broader in vivo functions remain largely unexplored. Here, we show that TIS are primarily phagocytosed by macrophages and dendritic cells, persist intracellularly for several days, and reprogram these cells in a manner distinct from LPS. TIS upregulate genes involved in metabolism, proliferation, and anti-inflammatory responses, and promote immune cell recruitment, including eosinophils. Notably, TIS induce minimal immune activation upon initial exposure but trigger a rapid and robust response upon secondary administration, indicating a priming effect reminiscent of adaptive immunity. In an MC38 colon cancer model, TIS treatment resulted in near-complete tumor suppression and durable protection upon rechallenge, highlighting their potential as a potent and long-lasting immunotherapeutic platform.