Chemical anchoring of immunotherapeutic drugs within senescent tumor cells overcomes senescence-driven immunotherapy resistance

Multidrug resistance (MDR) compromises cancer treatment efficacy and leads to therapeutic failure. Therapy-induced senescence further complicates MDR through senescence-enhanced drug efflux and senescence-associated secretory phenotypes (SASPs), remaining a huge challenge. Here, we develop a self-generative senescence-associated β-galactosidase (SA-β-gal)-initiated chemical anchoring of lysosomal protein approach to counteract drug efflux and reprogram SASPs. A senescence-tumor-targeted immunotherapeutic drug (DN-Ghcy) is fabricated by a SA-β-gal-activatable bio-orthogonal receptor (Ghcy) and an engineered immunostimulatory prodrug (DN, an indoleamine 2,3-dioxygenase (IDO) inhibitor conjugated to a PD-L1 binding peptide). DN-Ghcy is selectively immobilized in senescent tumor cells via SA-β-gal-catalyzed bio-orthogonal nano-receptor, enabling drug retention and bypassing transporter-mediated efflux. Under near-infrared irradiation, DN-Ghcy concurrently mediates degradation of PD-L1, release of IDO inhibitor, and disruption of lysosomal integrity. This strategy reverses immunotherapy resistance in female mice with senescent tumors, establishing a promising modality to overcome senescence-driven immunotherapy resistance.