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Stromal cells can adopt new phenotypes to promote tumor cell invasion. A deep understanding of the signaling pathways involved in cell\u2010to\u2010cell and cell\u2010to\u2010ECM interactions is needed to design effective intervention strategies that might interrupt these interactions. In this review, we describe the tumor microenvironment (TME) components and associated therapeutics. We discuss the clinical advances in the prevalent and newly discovered signaling pathways in the TME, the immune checkpoints and immunosuppressive chemokines, and currently used inhibitors targeting these pathways. These include both intrinsic and non\u2010autonomous tumor cell signaling pathways in the TME: protein kinase C (PKC) signaling, Notch, and transforming growth factor (TGF\u2010\u03b2) signaling, Endoplasmic Reticulum (ER) stress response, lactate signaling, Metabolic reprogramming, cyclic GMP\u2013AMP synthase (cGAS)\u2013stimulator of interferon genes (STING) and Siglec signaling pathways. We also discuss the recent advances in Programmed Cell Death Protein 1 (PD\u20101), Cytotoxic T\u2010Lymphocyte Associated Protein 4 (CTLA4), T\u2010cell immunoglobulin mucin\u20103 (TIM\u20103) and Lymphocyte Activating Gene 3 (LAG3) immune checkpoint inhibitors along with the C\u2010C chemokine receptor 4 (CCR4)\u2010 C\u2010C class chemokines 22 (CCL22)\/ and 17 (CCL17), C\u2010C chemokine receptor type 2 (CCR2)\u2010 chemokine (C\u2010C motif) ligand 2 (CCL2), C\u2010C chemokine receptor type 5 (CCR5)\u2010 chemokine (C\u2010C motif) ligand 3 (CCL3) chemokine signaling axis in the TME. In addition, this review provides a holistic understanding of the TME as we discuss the three\u2010dimensional and microfluidic models of the TME, which are believed to recapitulate the original characteristics of the patient tumor and hence may be used as a platform to study new mechanisms and screen for various anti\u2010cancer therapies. We further discuss the systemic influences of gut microbiota in TME reprogramming and treatment response. Overall, this review provides a comprehensive analysis of the diverse and most critical signaling pathways in the TME, highlighting the associated newest and critical preclinical and clinical studies along with their underlying biology. We highlight the importance of the most recent technologies of microfluidics and lab\u2010on\u2010chip models for TME research and also present an overview of extrinsic factors, such as the inhabitant human microbiome, which have the potential to modulate TME biology and drug responses.<\/jats:p>","DOI":"10.1002\/cac2.12416","type":"journal-article","created":{"date-parts":[[2023,4,3]],"date-time":"2023-04-03T00:29:46Z","timestamp":1680481786000},"page":"525-561","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":322,"title":["Tumor microenvironment signaling and therapeutics in cancer progression"],"prefix":"10.34133","volume":"43","author":[{"given":"Anshika","family":"Goenka","sequence":"first","affiliation":[{"name":"Northwestern University Feinberg School of Medicine","place":["Chicago, 60611, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8860-0339","authenticated-orcid":false,"given":"Fatima","family":"Khan","sequence":"additional","affiliation":[{"name":"Northwestern University","place":["Chicago, 60611, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bhupender","family":"Verma","sequence":"additional","affiliation":[{"name":"Harvard Medical School","place":["Boston, 02114, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Priyanka","family":"Sinha","sequence":"additional","affiliation":[{"name":"Massachusetts General Hospital, Harvard Medical School","place":["Charlestown, 02129, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Crismita C.","family":"Dmello","sequence":"additional","affiliation":[{"name":"Northwestern University","place":["Chicago, 60611, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manasi P.","family":"Jogalekar","sequence":"additional","affiliation":[{"name":"University of California San Francisco","place":["San Francisco, 94143, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prakash","family":"Gangadaran","sequence":"additional","affiliation":[{"name":"Kyungpook National University","place":["Daegu, 41944, South Korea"]},{"name":"School of Medicine, Kyungpook National University, Kyungpook National University Hospital","place":["Daegu, 41944, South Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7700-3929","authenticated-orcid":false,"given":"Byeong\u2010Cheol","family":"Ahn","sequence":"additional","affiliation":[{"name":"Kyungpook National University","place":["Daegu, 41944, South Korea"]},{"name":"School of Medicine, Kyungpook National University, Kyungpook National University Hospital","place":["Daegu, 41944, South Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","published-online":{"date-parts":[[2023,4,2]]},"reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-018-0006-7"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.02.013"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-20-1808"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-020-00449-x"},{"issue":"4","key":"e_1_3_2_6_2","first-page":"215","article-title":"Host tissue determinants of tumour immunity","volume":"19","author":"Salmon H","year":"2019","unstructured":"Salmon H, Remark R, Gnjatic S, Merad M. 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