Abstract
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.
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All generated data supporting this work are available in the main article, supplementary information or source data file. Source data are provided in this paper.
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Acknowledgements
This work was financially supported by the National Natural Science Foundation of China (No. 52333014, 22575086) and the Science and Technology Commission of Shanghai Municipality (No. 24520713200 and BJKJ2024054).
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W.H., J.T., and W.Z. designed and supervised the study. W.H., J.C., and N.A. performed in vitro experiments and animal experiments and analyzed data. W.H., J.C., N.A., J.T., and W.Z. participated in discussions, provided intellectual input and wrote the paper.
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Huang, W., Chen, J., Ali, N. et al. Chemical anchoring of immunotherapeutic drugs within senescent tumor cells overcomes senescence-driven immunotherapy resistance. Nat Commun (2026). https://doi.org/10.1038/s41467-026-71549-y
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DOI: https://doi.org/10.1038/s41467-026-71549-y
