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The reciprocal crosstalk between cancer cells and the tumor microenvironment (TME) shapes the cancer pathophysiome in a way that renders it uniquely suited for immune tolerance, angiogenesis, metastasis, and therapy resistance. This dynamic interaction involves a dramatic reconstruction of the transcriptomic landscape of tumors by altering the synthesis, modifications, stability, and processing of gene readouts. In this review, we categorically evaluate the influence of TME components, encompassing a myriad of resident and infiltrating cells, signaling molecules, extracellular vesicles, extracellular matrix, and blood vessels, in orchestrating the cancer\u2010specific metabolism and diversity of both mRNA and noncoding RNA, including micro RNA, long noncoding RNA, circular RNA among others. We also highlight the transcriptomic adaptations in response to the physicochemical idiosyncrasies of TME, which include tumor hypoxia, extracellular acidosis, and osmotic stress. Finally, we provide a nuanced analysis of existing and prospective therapeutics targeting TME to ameliorate cancer\u2010associated RNA metabolism, consequently thwarting the cancer progression.<\/jats:p><jats:p>This article is categorized under:<jats:list list-type=\"simple\">\n<jats:list-item><jats:p>RNA Processing &gt; Splicing Regulation\/Alternative Splicing<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>RNA Turnover and Surveillance &gt; Regulation of RNA Stability<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>RNA in Disease and Development &gt; RNA in Disease<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p>","DOI":"10.1002\/wrna.1676","type":"journal-article","created":{"date-parts":[[2021,6,10]],"date-time":"2021-06-10T21:18:07Z","timestamp":1623359887000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Interplay within tumor microenvironment orchestrates neoplastic <scp>RNA<\/scp> 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