Non‐Engineered Physiologically Modulated Nanovesicles Augment Antitumor Immune Responses via Dual‐Pathway T Cell Activation

ABSTRACT The therapeutic efficacy of cancer vaccines is critically contingent upon CD8 + T cell‐mediated antitumor immunity, but the effectiveness is hindered due to insufficient T cell activation. Inspired by the close interplay between cellular physiological states and immunoregulatory functions, we propose ASCENT, a nanovaccine platform integrating nanovesicles derived from activated platelets and senescent tumor cells to naturally co‐present antigens and co‐stimulatory molecules, thereby enabling dual‐pathway T cell activation. Specifically, senescent tumor cells promote antigen presentation via upregulated major histocompatibility complex‐I (MHC‐I) molecules, whereas activated platelets increase the surface expression of CD40L and OX40L, thereby enhancing immune activation. Thus, without genetic or chemical engineering, ASCENT can effectively stimulate CD8 + T cells through both antigen self‐presentation and dendritic cell‐mediated antigen presentation, ultimately eliciting robust immune responses. This non‐engineered, physiologically modulated nanovaccine exhibits broad‐spectrum antitumor activity while simultaneously inducing durable systemic immune memory to effectively suppress tumor recurrence and metastasis. Overall, the ASCENT nanovaccine provides new perspectives on rational vaccine design, emphasizing the importance of engaging both direct and indirect T cell activation in reinforcing cancer immunotherapy.