Intratumoral DCs exposed to chronic inflammatory and immunosuppressive signals show impaired T cell priming capacity, resulting in impaired tumor immunity. Efforts to overcome this deficit led to the development of ex vivo protocols to generate DCs with strong and sustained immunogenic functions. Here, we report that DCs matured in the presence of prostaglandin E₂ (PGE₂), a tumor-associated inhibitory factor, and α‑type‑1‑polarized dendritic cells (αDC1s) matured in the conditions that mimic acute viral infections, both take up and cross-present cancer cells, but generate different antigenic peptide epitopes and induce different patterns of tumor-specific CTL responses. αDC1s exhibited marked upregulation of genes associated with antigen processing and presentation machinery, along with increased expression of Th1/CTL/NK cell-activating factors, and unique transcription factors characteristic of cDC1s. Cancer cell-loaded αDC1s efficiently primed CTLs with much broader repertoire of diverse T‑cell receptors and enhanced recognition and killing of cancer cells. Our study identifies a new mechanism of tumor-associated immune dysfunction and potential targets for immune intervention in cancer, autoimmunity and inflammatory conditions.