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The field of ACT has been driven forward by the clinical success of CD19\u2010CAR therapy against various advanced B\u2010cell malignancies, including curative responses for some leukemia patients. However, relapse remains problematic, in particular for lymphoma. Moreover, for a variety of reasons, relative limited efficacy has been demonstrated for ACT of non\u2010hematological solid tumors. Indeed, in addition to pre\u2010infusion challenges including lymphocyte collection and manufacturing, ACT failure can be attributed to several biological processes post\u2010transfer including, (i) inefficient tumor trafficking, infiltration, expansion and retention, (ii) chronic antigen exposure coupled with insufficient costimulation resulting in T\u2010cell exhaustion, (iii) a range of barriers in the tumor microenvironment (TME) mediated by both tumor cells and suppressive immune infiltrate, (iv) tumor antigen heterogeneity and loss, or down\u2010regulation of antigen presentation machinery, (v) gain of tumor intrinsic mechanisms of resistance such as to apoptosis, and (vi) various forms of toxicity and other adverse events in patients. Affinity\u2010optimized TCRs can improve T\u2010cell function and innovative CAR designs as well as gene\u2010modification strategies can be used to coengineer specificity, safety, and function into T cells. Coengineering strategies can be designed not only to directly support the transferred T cells, but also to block suppressive barriers in the TME and harness endogenous innate and adaptive immunity. Here, we review a selection of the remarkable T\u2010cell coengineering strategies, including of tools, receptors, and gene\u2010cargo, that have been developed in recent years to augment tumor control by ACT, more and more of which are advancing to the clinic.<\/jats:p>","DOI":"10.1111\/imr.13252","type":"journal-article","created":{"date-parts":[[2023,8,7]],"date-time":"2023-08-07T08:57:20Z","timestamp":1691398640000},"page":"166-198","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Coengineering specificity, safety, and function into T cells for cancer immunotherapy"],"prefix":"10.1111","volume":"320","author":[{"given":"Greta Maria Paola","family":"Giordano\u00a0Attianese","sequence":"first","affiliation":[{"name":"Department of Oncology, Ludwig Institute for Cancer Research Lausanne Lausanne University Hospital and University of Lausanne  Lausanne 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