The tumor stroma, a key component of the tumor microenvironment (TME), is a key determinant of response and resistance to cancer treatment. The stromal cells, extracellular matrix (ECM), and blood vessels influence cancer cell response to therapy and play key roles in tumor relapse and therapeutic outcomes. Of the stromal cells present in the TME, much attention has been given to cancer-associated fibroblasts (CAFs) as they are the most abundant and important in cancer initiation, progression, and therapy resistance. Besides releasing several factors, CAFs also synthesize the ECM, a key component of the tumor stroma. In this expert review, we examine the role of CAFs in the regulation of tumor cell behavior and reveal how CAF-derived factors and signaling influence tumor cell heterogeneity and development of novel strategies to combat cancer. Importantly, CAFs display both phenotypic and functional heterogeneity, with significant ramifications on CAF-directed therapies. Principal anti-cancer therapies targeting CAFs take the form of: (1) CAFs' ablation through use of immunotherapies, (2) re-education of CAFs to normalize the cells, (3) cellular therapies involving CAFs delivering drugs such as oncolytic adenoviruses, and (4) stromal depletion via targeting the ECM and its related signaling. The CAFs' heterogeneity could be a result of different cellular origins and the cancer-specific tumor microenvironmental effects, underscoring the need for further multiomics and biochemical studies on CAFs and the subsets. Lastly, we present recent advances in therapeutic targeting of CAFs and the success of such endeavors or their lack thereof. We recommend that to advance global public health and personalized medicine, treatments in the oncology clinic should be combinatorial in nature, strategically targeting both cancer cells and stromal cells, and their interactions.

中文翻译：

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肿瘤微环境中与癌症相关的成纤维细胞的体系结构：绘制其起源，异质性以及在抗癌治疗中的作用。

肿瘤基质是肿瘤微环境（TME）的关键组成部分，是决定癌症治疗反应和耐药性的关键因素。基质细胞，细胞外基质（ECM）和血管会影响癌细胞对治疗的反应，并在肿瘤复发和治疗结果中发挥关键作用。在TME中存在的基质细胞中，与癌症相关的成纤维细胞（CAF）已引起了很多关注，因为它们在癌症的发生，发展和治疗耐药性方面最为丰富和重要。除了释放多种因素外，CAF还合成了ECM，ECM是肿瘤基质的关键成分。在此专家审查中，我们检查了CAF在调节肿瘤细胞行为中的作用，并揭示了CAF衍生的因子和信号传导如何影响肿瘤细胞的异质性以及抗癌新策略的发展。重要的是，CAF表现出表型和功能上的异质性，对CAF指导的疗法有明显的影响。针对CAF的主要抗癌疗法的形式为：（1）通过使用免疫疗法消融CAF；（2）对CAF进行再教育以使细胞正常化；（3）涉及CAF递送溶瘤腺病毒等药物的细胞疗法； （4）通过靶向ECM及其相关信号传导进行基质耗竭。CAFs的异质性可能是不同细胞起源和癌症特异性肿瘤微环境效应的结果，从而强调了需要对CAFs及其子集进行进一步的多组学和生化研究。最后，我们介绍了CAFs靶向治疗的最新进展以及此类努力的成功与否。