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Previously, we reported that the administration of a p62/SQSTM1-encoding plasmid demonstrates high safety and clinical benefits for human cancer patients, having also suppressed tumor growth and metastasis in dogs and mouse models. Here we investigated the mechanistic aspects of these effects. In mammary tumors bearing-dogs, p62 plasmid i.m. injections reduced tumor volumes, and reverted tumor grade to less aggressive lesions in 5 out of 6 animals, with one carcinoma switching to benign adenoma. The treatment increased levels of alpha-SMA in stroma cells and collagen 3 in the extracellular matrix, both of which correlate with a good clinical prognosis. p62 treatment also increased the abundance of intratumoral T-cell. To test the role of adaptive immunity, we compared protective effects of the plasmid against B16 melanoma in wild type C57BL/6J mice and in the corresponding SCID strain lacking lymphocytes. The plasmid was only protective in the wild type strain. Also, p62 plasmid amplified anti-tumor effect of adoptive T-cell transfer from tumor-bearing animals to animals challenged with the same tumors. We conclude that the plasmid acts indirectly via re-modeling of the tumor microenvironment, making it more favorable for increased anti-cancer immunity. Thus, the p62-encoding plasmid might be a new adjuvant for cancer treatments. Key words: Canine breast tumors, Tumor microenvironment, Anti-cancer immunity, p62 / SQSTM1, DNA plasmid, clinical trial, extracellular matrix.