Immune checkpoint inhibitors have revolutionised cancer therapy, yet their success depends on pre-existing antitumor immunity, often poorly represented in tumours like triple-negative breast cancer (TNBC) and glioblastoma (GBM). Cancer vaccines offer a strategy to elicit de novo tumour-specific T cells, but clinical application is limited by the challenge of identifying effective antigens and suitable delivery systems. Whole tumour cell lysates are attractive because they provide a broad antigenic repertoire, particularly in heterogeneous cancers such as TNBC and GBM. However, standard lysates are poorly immunogenic. To overcome this, we have exploited the immunogenic cell death (ICD) induced by 9-cis-retinoic acid and interferon-alpha (RAI) to generate lysates with superior potency. The immunogenicity of RAI-treated tumour cell lysates was demonstrated in both in vitro assays and in vivo models of TNBC and GBM. Notably, RAI treatment significantly enhanced the immunogenicity of tumour lysates compared with conventional lysates obtained from untreated dead cells or from lysates generated with the prototypic ICD inducer, doxorubicin (DOXO). Using a nanoparticle-based delivery system that selectively targets antigens to cross-presenting Clec9A⁺ dendritic cells in vivo, we demonstrated superior therapeutic efficacy of RAI-lysate-based vaccines in both murine and humanised orthotopic models of TNBC and GBM. Furthermore, proteomic and immunopeptidomic analyses revealed distinct antigenic profiles among untreated, DOXO-, and RAI-treated lysates, providing mechanistic insights into the enhanced therapeutic efficacy of RAI-lysate-based vaccines. These findings support the use of RAI-induced tumour cell lysates as improved antigen formulations for the treatment of poorly immunogenic and heterogeneous tumours such as TNBCs and GBM.