Inducing immunogenic cell death (ICD) by sonodynamic therapy (SDT) is promising for cancer immunotherapy, which however is inefficient due to oxygen depletion that compromises SDT effect and mediates recruitment of immunosuppressive myeloid-derived suppressor cells (MDSCs). The fabrication of sono-activatable semiconducting polymer nanopartners (SPN ) to simultaneously augment ICD and alleviate MDSCs for immunotherapy is reported. A sonodynamic semiconducting polymer, hydrophobic hypoxia-responsive tirapazamine (TPZ)-conjugate, and MDSC-targeting drug (ibrutinib) are encapsulated inside such SPN with surface shell of a singlet oxygen ( O )-cleavable amphiphilic polymer. TPZ and ibrutinib serve as drug partners to enlarge immunotherapeutic effect. Upon sono-activation, SPN generate O to break O -cleavable polymers for in situ liberations of TPZ-conjugate and ibrutinib in tumor sites, and oxygen is consumed to create severe hypoxic tumor microenvironment, in which, TPZ-conjugate is activated for augmenting ICD action, while ibrutinib alleviates MDSCs for promoting antitumor immunological effect. In a bilateral tumor mouse model, SPN -mediated sono-activatable immunotherapy results in growth restraints of primary and distant tumors and noteworthy precaution of tumor metastases. This study thus provides a sono-activatable immunotherapeutic strategy with high precision and safety for cancer via overcoming post-treatment hypoxia and targeting MDSCs.