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The combination of cuproptosis and immune checkpoint inhibition has shown promise in treating malignant tumors. However, it remains a challenge to deliver copper ions and immune checkpoint inhibitors efficiently and simultaneously to tumors. Herein, a mitochondria‐targeted nanoscale coordination polymer particle, Cu/TI, comprising Cu(II), and a triphenylphosphonium conjugate of 5‐carboxy‐8‐hydroxyquinoline (TI), for effective cuproptosis induction and programmed cell death‐1 (PD‐L1) downregulation is reported. Upon systemic administration, Cu/TI efficiently accumulates in tumor tissues to induce immunogenic cancer cell death and reduce PD‐L1 expression. Consequently, Cu/TI promotes the intratumoral infiltration and activation of cytotoxic T lymphocytes to greatly inhibit tumor progression of colorectal carcinoma and triple‐negative breast cancer in mouse models without causing obvious side effects. Mitochondria‐targeted core–shell nanoparticle Cu/TI for simultaneous cuproptosis induction and PD‐L1 downregulation is reported. Cu/TI exhibits prolonged blood circulation and high tumor uptake to induce immunogenic cancer cell death and reduce PD‐L1 expression in vivo, thereby effectively enhancing the infiltration and activation of cytotoxic T lymphocytes to elicit potent antitumor effects in mouse models without causing obvious side effects.

Immune evasion behavior and immunosuppressive characteristics of tumor extensively impede the immune initiation effect of therapy triggered immunogenic cell death (ICD). In this work, a carrier-adjuvanted immunostimulator (designated as CoCeC) is developed to boost photodynamic immunotherapy by downregulating programmed death ligand 1 (PD-L1) and impairing adenosine triphosphate (ATP) hydrolysis. Among these, the crosslinked chitosan oligosaccharide is applied as the drug carrier for delivery of Ce6 and Ceritinib, which also serves as an immune adjuvant to downregulate PD-L1. Meanwhile, the robust photodynamic therapy (PDT) of CoCeC exhibits lethal toxicity against tumor cells to induce ICD and release damage-associated molecular patterns (DAMPs), which can also impair ATP hydrolysis by blocking CD39. In vitro and in vivo results demonstrate the robust therapeutic efficacy of CoCeC to suppress primary tumor growth and activate a superior immune elimination against lung metastasis by amplifying the immune initiation of ICD with the assistance of immune adjuvants. This work provides a self-adjuvanted strategy to enhance the immune response of therapy induced ICD, which is promising to activate systemic antitumor immunity in consideration of the complicated immunosuppressive factors.

Ubiquitin-specific peptidase 22 (Usp22) cleaves ubiquitin moieties from numerous proteins, including histone H2B and transcription factors. Recently, it was reported that Usp22 acts as a negative regulator of interferon-dependent responses. In the current study, we investigated the role of Usp22 deficiency in acute viral infection with lymphocytic choriomeningitis virus (LCMV). We found that the lack of Usp22 on bone marrow-derived cells (Usp22fl/fl Vav1-Cre mice) reduced the induction of type I and II interferons. A limited type I interferon response did not influence virus replication. However, restricted expression of PD-L1 led to increased frequencies of functional virus-specific CD8+ T cells and rapid death of Usp22-deficient mice. CD8+ T cell depletion experiments revealed that accelerated CD8+ T cells were responsible for enhanced lethality in Usp22 deficient mice. In conclusion, we found that the lack of Usp22 generated a pathological CD8+ T cell response, which gave rise to severe disease in mice.

Therapeutic monoclonal antibodies (mAb) targeting the immune checkpoint inhibitor programmed cell death protein 1 (PD-1) have achieved considerable clinical success in anti-cancer therapy through relieving T cell exhaustion. Blockade of PD-1 interaction with its ligands PD-L1 and PD-L2 is an important determinant in promoting the functional recovery of exhausted T cells. Here, we show that anti-PD-1 mAbs act through an alternative mechanism leading to the downregulation of PD-1 surface expression on memory CD4 + and CD8 + T cells. PD-1 receptor downregulation is a distinct process from receptor endocytosis and occurs in a CD14 + monocyte dependent manner with the CD64/Fcγ receptor I acting as the primary factor for this T cell extrinsic process. Importantly, downregulation of surface PD-1 strongly enhances antigen-specific functional recovery of exhausted PD-1 + CD8 + T cells. Our study demonstrates a novel mechanism for reducing cell surface levels of PD-1 and limiting the inhibitory targeting by PD-L1/2 and thereby enhancing the efficacy of anti-PD-1 Ab in restoring T cell functionality.