Wenshe Sun,1– 3,* Shaowei Xie,4,* Shi Feng Liu,1,* Xiaokun Hu,1 Dongming Xing1,2 

1The Affiliated Hospital of Qingdao University, Qingdao, 266071, People’s Republic of China; 2Qingdao Cancer Institute, Qingdao University, Qingdao, 266071, People’s Republic of China; 3Medical Science and Technology Innovation Center, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, People’s Republic of China; 4Department of Ultrasound, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Xiaokun Hu; Dongming Xing, The Affiliated Hospital of Qingdao University, Qingdao, 266071, People’s Republic of China, Email huxiaokun770@163.com; xdm_tsinghua@163.com

Abstract: Typical physiological characteristics of tumors, such as weak acidity, low oxygen content, and upregulation of certain enzymes in the tumor microenvironment (TME), provide survival advantages when exposed to targeted attacks by drugs and responsive nanomedicines. Consequently, cancer treatment has significantly progressed in recent years. However, the evolution and adaptation of tumor characteristics still pose many challenges for current treatment methods. Therefore, efficient and precise cancer treatments require an understanding of the heterogeneity degree of various factors in cancer cells during tumor evolution to exploit the typical TME characteristics and manage the mutation process. The highly heterogeneous tumor and infiltrating stromal cells, immune cells, and extracellular components collectively form a unique TME, which plays a crucial role in tumor malignancy, including proliferation, invasion, metastasis, and immune escape. Therefore, the development of new treatment methods that can adapt to the evolutionary characteristics of tumors has become an intense focus in current cancer treatment research. This paper explores the latest understanding of cancer evolution, focusing on how tumors use new antigens to shape their “new faces”; how immune system cells, such as cytotoxic T cells, regulatory T cells, macrophages, and natural killer cells, help tumors become “invisible”, that is, immune escape; whether the diverse cancer-associated fibroblasts provide support and coordination for tumors; and whether it is possible to attack tumors in reverse. This paper discusses the limitations of targeted therapy driven by tumor evolution factors and explores future strategies and the potential of intelligent nanomedicines, including the systematic coordination of tumor evolution factors and adaptive methods, to meet this therapeutic challenge.

Keywords: smart nanomedicine, tumor evolution, immune cells, fibroblasts