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The interaction between a tumor and the tumor microenvironment (TME) plays a key role in tumorigenesis and tumor progression. Ubiquitination, a crucial post‑translational modification for regulating protein degradation and turnover, plays a role in regulating the crosstalk between a tumor and the TME. Thus, identifying the roles of ubiquitination in the process may assist researchers to investigate the mechanisms underlying tumorigenesis and tumor progression. In the present review article, new insights into the substrates for ubiquitination that are involved in the regulation of hypoxic environments, angiogenesis, chronic inflammation‑mediated tumor formation, and the function of cancer‑associated fibroblasts and infiltrating immune cells (tumor‑associated macrophages, T‑cells, myeloid‑derived suppressor cells, dendritic cells, and natural killer cells) are summarized. In addition, the potential targets of the ubiquitination proteasome system within the TME for cancer therapy and their therapeutic effects are reviewed and discussed.