PMID- 37005490 OWN - NLM STAT- MEDLINE DCOM- 20230515 LR - 20231101 IS - 2523-3548 (Electronic) IS - 2523-3548 (Linking) VI - 43 IP - 5 DP - 2023 May TI - Tumor microenvironment signaling and therapeutics in cancer progression. PG - 525-561 LID - 10.1002/cac2.12416 [doi] AB - Tumor development and metastasis are facilitated by the complex interactions between cancer cells and their microenvironment, which comprises stromal cells and extracellular matrix (ECM) components, among other factors. Stromal cells can adopt new phenotypes to promote tumor cell invasion. A deep understanding of the signaling pathways involved in cell-to-cell and cell-to-ECM 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-autonomous tumor cell signaling pathways in the TME: protein kinase C (PKC) signaling, Notch, and transforming growth factor (TGF-beta) signaling, Endoplasmic Reticulum (ER) stress response, lactate signaling, Metabolic reprogramming, cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) and Siglec signaling pathways. We also discuss the recent advances in Programmed Cell Death Protein 1 (PD-1), Cytotoxic T-Lymphocyte Associated Protein 4 (CTLA4), T-cell immunoglobulin mucin-3 (TIM-3) and Lymphocyte Activating Gene 3 (LAG3) immune checkpoint inhibitors along with the C-C chemokine receptor 4 (CCR4)- C-C class chemokines 22 (CCL22)/ and 17 (CCL17), C-C chemokine receptor type 2 (CCR2)- chemokine (C-C motif) ligand 2 (CCL2), C-C chemokine receptor type 5 (CCR5)- chemokine (C-C 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-dimensional 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-cancer 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-on-chip 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. CI - (c) 2023 The Authors. Cancer Communications published by John Wiley & Sons Australia, Ltd. on behalf of Sun Yat-sen University Cancer Center. FAU - Goenka, Anshika AU - Goenka A AD - The Ken & Ruth Davee Department of Neurology, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, 60611, IL, USA. FAU - Khan, Fatima AU - Khan F AUID- ORCID: 0000-0002-8860-0339 AD - Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, 60611, IL, USA. FAU - Verma, Bhupender AU - Verma B AD - Department of Ophthalmology, Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, 02114, MA, USA. FAU - Sinha, Priyanka AU - Sinha P AD - Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, 02129, MA, USA. FAU - Dmello, Crismita C AU - Dmello CC AD - Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, 60611, IL, USA. FAU - Jogalekar, Manasi P AU - Jogalekar MP AD - Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, 94143, CA, USA. FAU - Gangadaran, Prakash AU - Gangadaran P AD - BK21 FOUR KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, Department of Biomedical Science, School of Medicine, Kyungpook National University, Daegu, 41944, South Korea. AD - Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, 41944, South Korea. FAU - Ahn, Byeong-Cheol AU - Ahn BC AUID- ORCID: 0000-0001-7700-3929 AD - BK21 FOUR KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, Department of Biomedical Science, School of Medicine, Kyungpook National University, Daegu, 41944, South Korea. AD - Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, 41944, South Korea. LA - eng PT - Journal Article PT - Review DEP - 20230402 PL - United States TA - Cancer Commun (Lond) JT - Cancer communications (London, England) JID - 101723675 RN - 0 (Receptors, Chemokine) RN - 0 (Chemokines) SB - IM MH - Humans MH - *Tumor Microenvironment MH - *Neoplasms/metabolism MH - Signal Transduction MH - Neoplastic Processes MH - Receptors, Chemokine/therapeutic use MH - Chemokines/pharmacology/therapeutic use PMC - PMC10174093 OTO - NOTNLM OT - 3D-model OT - cancer therapy OT - gut microbiota OT - immune signaling OT - metabolism OT - signaling OT - tumor microenvironment COIS- The authors declare that the research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2023/04/04 06:00 MHDA- 2023/05/15 06:42 PMCR- 2023/04/02 CRDT- 2023/04/03 00:40 PHST- 2023/02/22 00:00 [revised] PHST- 2022/10/24 00:00 [received] PHST- 2023/03/20 00:00 [accepted] PHST- 2023/05/15 06:42 [medline] PHST- 2023/04/04 06:00 [pubmed] PHST- 2023/04/03 00:40 [entrez] PHST- 2023/04/02 00:00 [pmc-release] AID - CAC212416 [pii] AID - 10.1002/cac2.12416 [doi] PST - ppublish SO - Cancer Commun (Lond). 2023 May;43(5):525-561. doi: 10.1002/cac2.12416. Epub 2023 Apr 2.