Sono‐Activatable Semiconducting Polymer Nanoreshapers Multiply Remodel Tumor Microenvironment for Potent Immunotherapy of Orthotopic Pancreatic Cancer

Abstract Due to the complicated tumor microenvironment that compromises the efficacies of various therapies, the effective treatment of pancreatic cancer remains a big challenge. Sono‐activatable semiconducting polymer nanoreshapers (SPN DN H) are constructed to multiply remodel tumor microenvironment of orthotopic pancreatic cancer for potent immunotherapy. SPN DN H contain a semiconducting polymer, hydrogen sulfide (H 2 S) donor, and indoleamine 2,3‐dioxygenase (IDO) inhibitor (NLG919), which are encapsulated by singlet oxygen ( 1 O 2 )‐responsive shells with modification of hyaluronidase (HAase). After accumulation in orthotopic pancreatic tumor sites, SPN DN H degrade the major content of tumor microenvironment hyaluronic acid to promote nanoparticle enrichment and immune cell infiltration, and also release H 2 S to relieve tumor hypoxia via inhibiting mitochondrion functions. Moreover, the relieved hypoxia enables amplified sonodynamic therapy (SDT) under ultrasound (US) irradiation with generation of 1 O 2 , which leads to immunogenic cell death (ICD) and destruction of 1 O 2 ‐responsive components to realize sono‐activatable NLG919 release for reversing IDO‐based immunosuppression. Through such a multiple remodeling mechanism, a potent antitumor immunological effect is triggered after SPN DN H‐based treatment. Therefore, the growths of orthotopic pancreatic tumors in mouse models are almost inhibited and tumor metastases are effectively restricted. This study offers a sono‐activatable nanoplatform to multiply remodel tumor microenvironment for effective and precise immunotherapy of deep‐tissue orthotopic tumors.