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Hot tumors, characterized by heightened immune activity and responsiveness to immune checkpoint inhibitors (ICIs), stand in stark contrast to cold tumors, which lack immune infiltration and remain resistant to therapy. To overcome immune evasion mechanisms employed by tumor cells, novel immunologic modulators have emerged, particularly ICIs targeting cytotoxic T\u2010lymphocyte\u2010associated protein 4 (CTLA\u20104) and programmed cell death protein 1\/programmed death\u2010ligand 1(PD\u20101\/PD\u2010L1). These agents disrupt inhibitory signals and reactivate the immune system, transforming cold tumors into hot ones and promoting effective antitumor responses. However, challenges persist, including primary resistance to immunotherapy, autoimmune side effects, and tumor response heterogeneity. Addressing these challenges requires innovative strategies, deeper mechanistic insights, and a combination of immune interventions to enhance the effectiveness of immunotherapies. In the landscape of cancer medicine, where immune cold tumors represent a formidable hurdle, understanding the TME and harnessing its potential to reprogram the immune response is paramount. This review sheds light on current advancements and future directions in the quest for more effective and safer cancer treatment strategies, offering hope for patients with immune\u2010resistant tumors.<\/jats:p>","DOI":"10.1002\/cac2.12539","type":"journal-article","created":{"date-parts":[[2024,3,29]],"date-time":"2024-03-29T13:04:06Z","timestamp":1711717446000},"page":"521-553","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":377,"title":["Immunologic tumor microenvironment modulators for turning cold tumors hot"],"prefix":"10.34133","volume":"44","author":[{"given":"Gholam\u2010Reza","family":"Khosravi","sequence":"first","affiliation":[{"name":"School of Medicine","place":["Isfahan, Iran"]},{"name":"Isfahan University of Medical Sciences","place":["Isfahan, Iran"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samaneh","family":"Mostafavi","sequence":"additional","affiliation":[{"name":"Faculty of Medical Sciences","place":["Tehran, Iran"]},{"name":"Tarbiat Modares University","place":["Tehran, Iran"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanaz","family":"Bastan","sequence":"additional","affiliation":[{"name":"School of Medicine","place":["Isfahan, Iran"]},{"name":"Isfahan University of Medical Sciences","place":["Isfahan, Iran"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Narges","family":"Ebrahimi","sequence":"additional","affiliation":[{"name":"School of Medicine","place":["Isfahan, Iran"]},{"name":"Isfahan University of Medical Sciences","place":["Isfahan, Iran"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roya Safari","family":"Gharibvand","sequence":"additional","affiliation":[{"name":"School of Medicine","place":["Ahvaz, Iran"]},{"name":"Ahvaz Jundishapur University of Medical Sciences","place":["Ahvaz, Iran"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1910-9359","authenticated-orcid":false,"given":"Nahid","family":"Eskandari","sequence":"additional","affiliation":[{"name":"School of Medicine","place":["Isfahan, Iran"]},{"name":"Isfahan University of Medical Sciences","place":["Isfahan, Iran"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","published-online":{"date-parts":[[2024,3,29]]},"reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.apsb.2021.03.027"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3394"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1002\/cac2.12416"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature21349"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-15-1507"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-018-0007-y"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature14011"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2019.12.011"},{"issue":"11","key":"e_1_3_2_10_2","doi-asserted-by":"crossref","first-page":"5365","DOI":"10.7150\/thno.58390","article-title":"Turning cold tumors into hot tumors by improving T\u2010cell infiltration","volume":"11","author":"Liu Y\u2010T","year":"2021","unstructured":"Liu Y\u2010T, Sun Z\u2010J. 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