The AUTACE That Degrades KRAS and Engages CD8 + T Cells for the Treatment of KRAS/TP53 Co‐Mutant Tumors

ABSTRACT KRAS and TP53 co‐mutations are frequently associated with highly aggressive, therapy‐resistant cancers with limited treatment options. In this study, we have developed Autophagy‐Targeting Chimera–T‐cell Engager (AUTACE), a bifunctional nanoplatform composed of T‐cell receptor–engineered T (TCR‐T) cell–derived nanovesicles that display anti‐CD3 antibodies and encapsulate perfluoropentane (PFP) together with KPY, an autophagy‐targeting degrader active against mutant KRAS, for the treatment of KRAS/TP53 co‐mutant tumors. AUTACE targets tumors via TP53‐specific TCRs, elicits antitumor CD8 + T‐cell responses through surface anti‐CD3 antibodies, and employs low‐intensity focused ultrasound (LIFU) to trigger controlled release of KPY to degrade mutant KRAS. This achieved targeted tumor elimination. The therapeutic efficacy of AUTACE was validated in mice bearing PANC‐1 and MIA PaCa‐2 tumors. A comprehensive assessment of the post‐treatment tumor microenvironment revealed that KRAS degradation increased tumor‐derived CCL5 levels, thereby promoting CD8 + T‐cell recruitment and amplifying antitumor responses. Thus, AUTACE represents a promising strategy for the treatment of KRAS/TP53 co‐mutant tumors.