<p>The failure of tumour immunotherapy can be attributed to two primary factors: the limited immunogenicity of tumour cells and the immunosuppressive characteristics of the tumour microenvironment. Recent research indicates that cancer patients infected with respiratory viruses exhibit a positive antitumour response, as the activated host immune system. Here we show a bioorthogonal optimized virus immuno-nanomedicine (BOVIN) that uses nonpathogenic recombinant virus immuno-nanomedicine (VIN) for the targeted therapy of solid tumours. The influenza viruses (A/WSN/1933(WSN)) induce immunogenic cell death (ICD) in tumour cells by triggering a stress response mediated by integrated mitochondrial dysregulation. Furthermore, the surface modification of WSN with lactate oxidase enables the consumption of lactate to produce hydrogen peroxide, which synergistically enhance ICD activation. This leads to the attraction and significant activation of antigen-presenting cells in the tumour region through the exposure of calreticulin and secretion of high mobility group box 1. Additionally, the BOVIN triggers the tumour ICD, significantly enhances CD8⁺ T-cell tumour infiltration, strengthens the sensitivity of immune checkpoint blockers, and thus activates anti-tumour immune memory to effectively inhibit tumour recurrence after surgery. In conclusion, bioorthogonal nonpathogenic recombinant VIN reverses the immunosuppressed state of malignant cells, offering potential for improved tumour immunotherapy.</p>