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

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.