Chemoimmunotherapy has shown great potential to activate an immune response, but the immunosuppressive microenvironment associated with T cell exhaustion remains a challenge in cancer therapy. The proper immune‐modulatory strategy to provoke a robust immune response is to simultaneously regulate T‐cell exhaustion and infiltration. Here, a new kind of carrier‐free nanoparticle is developed to simultaneously deliver chemotherapeutic drug (doxorubicin, DOX), cytolytic peptide (melittin, MPI), and anti‐TOX small interfering RNA (thymocyte selection‐associated high mobility group box protein, TOX) using a fluorinated prodrug strategy. In this way, the enhanced immunogenic cell death (ICD) induced by the combination of DOX and MPI can act as “offense” signaling to increase CD8+ T‐cell infiltration, while the decreased TOX expression interfered with siTOX can serve as “defense” signaling to mitigate CD8+ T‐cell exhaustion. As a result, the integration of DOX, MPI, and siTOX in such a bifunctional system produced a potent antitumor immune response in liver cancer and metastasis, making it a promising delivery platform and effective strategy for converting “cold” tumors into “hot” ones.
Hepatocellular carcinoma (HCC) is one of the most fatal tumours worldwide and has a high recurrence rate. Nevertheless, the mechanism of HCC genesis remains partly unexplored, while the efficiency of HCC treatments remains limited. The present study analysed the expression of nuclear receptor subfamily 4 group A member 1 (NR4A1) in tumour‐infiltrating natural killer (NK) cells derived from both human patients with HCC and tumour‐bearing mouse models, as well as the features of NR4A1high and NR4A1low NK cells. In addition, knockout of NR4A1 by CRISPR/Cas9 and adoptive transfer experiments were applied to verify the function of NR4A1 in both tumour‐infiltrating NK cells and anti‐PD‐1 therapy. The present study found that NR4A1 was significantly highly expressed in tumour‐infiltrating NK cells, which mediated the dysfunction of tumour‐infiltrating NK cells by regulating the IFN‐γ/p‐STAT1/IRF1 signalling pathway. Knockout of NR4A1 in NK cells not only restored the antitumour function of NK cells but also enhanced the efficacy of anti‐PD‐1 therapy. The present findings suggest a regulatory role of NR4A1 in the immune progress of NK cells against HCC, which may provide a new direction for immunotherapies of HCC.
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