Vaccination-enabled immune readiness for checkpoint blockade

Immune checkpoint blockade has transformed cancer therapy by demonstrating that durable tumour control can be achieved through immune modulation rather than direct cytotoxicity. However, primary resistance remains the dominant clinical outcome across solid tumours, reflecting a fundamental limitation of checkpoint inhibitors: they do not initiate antitumour immunity, but amplify immune responses that are already underway. Here, we advance immune readiness as a unifying framework to explain primary resistance to immune checkpoint inhibitors. Immune readiness is defined as a dynamic and programmable host-tumour state characterised by competent innate sensing, type I interferon-driven myeloid activation, dendritic-cell licensing, coordinated antigen presentation, productive lymphocyte priming, and permissive inflammatory trafficking into tumour tissue. In the absence of these upstream processes, checkpoint blockade is biologically inconsequential, regardless of tumour antigenicity or checkpoint expression. Within this framework, therapeutic vaccination is positioned as a flexible immune-conditioning strategy that can induce, amplify, or synchronise immune readiness rather than as a direct cytotoxic modality or rigidly antecedent intervention. Tumour-directed, immune-modulatory, and tumour-agnostic vaccines may construct the immunological substrate required for checkpoint efficacy when integrated before, during, or in close temporal coordination with checkpoint blockade. Engineering immune readiness through vaccination-enabled immunotherapy offers a coherent strategy to overcome primary resistance and expand the therapeutic reach of cancer immunotherapy.