Core Viewpoint - The article discusses the evolution of the "Hallmarks of Cancer" theory, expanding from six to nine characteristics and introducing four dimensions to better understand cancer complexity [2][3]. Group 1: Evolution of Cancer Characteristics - In 2000, Douglas Hanahan and Robert Weinberg first proposed six hallmarks of cancer: sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis [5]. - In 2011, two additional hallmarks were added: deregulating cellular energetics and escaping immune destruction. By 2022, the ninth hallmark, "unlocking phenotypic plasticity," was introduced [6]. Group 2: Nine Hallmarks of Cancer - The newly added ninth hallmark refers to cancer cells' ability to change their identity and characteristics, explaining the diversity of cell types within tumors and their adaptability to treatment pressures [9]. Group 3: Four Dimensions of Cancer Complexity - The new framework categorizes cancer complexity into four dimensions: 1. The nine hallmarks themselves, which are core capabilities for cancer cell survival and development [11]. 2. Five enabling characteristics, including genomic instability, tumor-promoting inflammation, neural regulation, polymorphic microbiome, and non-mutational epigenetic reprogramming, which facilitate the acquisition of the nine hallmarks [12]. 3. Various cells in the tumor microenvironment, such as cancer cells, senescent cells, cancer-associated fibroblasts, neurons, endothelial cells, and immune cells, which assist cancer cells in acquiring necessary features [12]. 4. Systemic interactions, highlighting cancer as a systemic disease interacting with other parts of the body [13]. Group 4: Focus on Neural Regulation - "Cancer neuroscience" has emerged as a significant area of focus, revealing that nerves not only surround tumors but also communicate closely with cancer cells. In some cases, cancer cells form "synapse-like" connections with nerves, receiving growth signals through neurotransmitters [20][21]. Group 5: Microbiome's Role in Cancer - The microbiome, consisting of bacteria, fungi, and viruses, has a profound impact on cancer. The composition of an individual's microbiome can influence cancer development and treatment responses [22][23]. - The gut microbiome may affect the efficacy of cancer immunotherapy by modulating the immune system. Studies indicate that fecal transplants from responding patients can enhance treatment effects in non-responders [24][25]. Group 6: Future Directions in Cancer Treatment - Scientists propose a "feature-coordinated targeting" treatment strategy, aiming to target multiple cancer characteristics simultaneously to prevent the emergence of resistance mechanisms [26]. - Successful clinical examples include combinations of anti-angiogenic drugs with immune checkpoint inhibitors showing superior effects in certain cancers. Future treatments may involve combinations targeting different cancer features, guided by advancements in single-cell sequencing and spatial transcriptomics [30][31].