Don't be afraid if cancer has metastasized. What else can you do?

Figure 1. Metastatic Tumor Microenvironment^​1​

The composition of the tumor microenvironment (TME) is crucial for tumor growth and progression. However, deciphering the mechanism of interaction between the tumor and its environment is extremely challenging! The abundance of growth factors, cytokines, and other factors, as well as numerous signaling pathways involved in communication between these two entities, make this mechanism difficult to understand, and almost any outcome is possible. Therefore, the importance of the tumor microenvironment is evident, and an increasing number of studies have found that the environment of immune cells and the expression of immune regulatory receptors in the TME become more suppressed in metastatic tumors. It is believed that with more understanding, there will be more targeted treatment options for the tumor environment and combined tumor-environment therapies.  

Metastatic cancers such as breast cancer, prostate cancer, pancreatic cancer, colorectal cancer, and melanoma are currently research hotspots. Antitumor metastasis drugs are mainly divided into antibody drugs, small molecule inhibitors, peptides, and nucleic acids according to their molecular structure. Based on different mechanisms of action, they are further classified into the following categories:

(1) Anti-angiogenic therapy: Since metastasis relies on the growth of new blood vessels in primary and secondary tumors, drugs that inhibit angiogenesis, such as some angiogenesis factor inhibitors, can suppress metastasis. Currently, the combination of anti-angiogenic drugs with chemotherapy/radiotherapy is the most effective treatment method. Unfortunately, many tumors become resistant to anti-angiogenic therapy, so this is usually not a long-term solution.

(2) Metastasis inhibitors: Recent studies have identified a group of molecules that induce metastasis without affecting primary tumor growth. These molecules can inhibit cell death when cell adhesion is lost or enhance the ability of cells to migrate through the stroma. These molecules are crucial for different stages of metastasis. Inhibitors targeting these molecules are called metastatic suppressors, such as cell adhesion molecule antagonists and metalloproteinase inhibitors. Researchers hope that these molecules can become targets for anti-cancer/anti-metastasis therapy. In 2023, China Pharmaceutical University published a paper in Nature, reporting the discovery of a TRPV4 inhibitor, GL-V9, which significantly inhibits liver cancer metastasis. Preclinical studies have shown its strong anti-metastatic effect and low toxicity. This suggests that TRPV4 is a promising therapeutic target for preventing cancer metastasis, which requires further clinical research validation.

(3) Chinese herbal medicine: Alkaloids in compound prescriptions of Chinese herbal medicine, such as ginsenosides and paclitaxel, are believed to enhance immune function and may also have anti-metastatic effects.

(4) Others: In addition, immune-enhancing drugs or biologics, including interferon (IFN), short peptides, vaccines, IL-2, tumor necrosis factor, plant polysaccharides, and antioxidants, are also considered anti-metastatic drugs.

On April 13, 2023, Professor Karuna Ganesh of the Memorial Sloan Kettering Cancer Center, as the corresponding author, published a review article titled "Metastasis" in the top-tier journal Cell (IF score: 66.85), which comprehensively summarizes the latest advancements in tumor metastasis research.

Currently, there are three scenarios for the treatment of metastatic diseases: (1) When metastatic disease is suspected to be micrometastatic in the (neo-)adjuvant therapy setting, it cannot be detected by standard imaging and screening techniques, nor can it be intervened with conventional treatment methods. (2) Although multi-organ metastasis is largely incurable, selective local treatment for oligometastases can prolong life to some extent, such as surgical resection, radiotherapy, ablation, interventional therapy, etc., targeting metastatic lesions. (3) Multi-organ metastatic diseases are typically treated with systemic therapy, including chemotherapy, targeted therapy (such as small molecule inhibitors, antibodies, or antibody-drug conjugates), and immunotherapy.

Figure 2. Current treatment strategies for metastatic tumors< H294>【2】

Currently, although there are treatment plans for the second and third situations, the efficacy is often unsatisfactory. For the first situation, there is currently no good solution. In micrometastasis, the initiating cell (MIC) and immune surveillance are in a dynamic balance. Proliferating cells are often cleared by tissue resident or circulating immune cells, while dormant cells evade immune destruction. In oligometastasis, small tumors are infiltrated by tumor microenvironment (TME) resident cells and recruit immune cells. In multi organ metastasis, TME becomes increasingly immunosuppressive, capable of clearing tumor reactive immune cells or putting them into an immunosuppressive state.

Figure 3. Emerging Treatment Opportunities for Metastatic Tumors^[2]

How to eliminate these possible micro metastases while avoiding harm caused by overtreatment has become a common challenge for doctors and patients today. Among all emerging treatment methods, adoptive immune cell therapy has attracted attention due to its ability to help improve the body's immune system, completely eliminate residual "zombie" cells and small metastatic lesions in the body. Especially unmodified natural immune cells, they can rebuild and enhance the patient's own immune function, comprehensively identify, search, and kill diseased cells, effectively prevent tumor recurrence and metastasis, without causing damage to the body. The v-NKT cell therapy discovered by Zhang Minghui's experimental team belongs to the adoptive cell therapy in immunotherapy, which has the characteristic of broad-spectrum killing of tumor cells. Therefore, after the reduction of tumor burden (such as after surgery or radiotherapy and chemotherapy treatment), it is possible to effectively remove tumor cells that may remain in the body but cannot be detected by existing technological means, thereby effectively preventing tumor recurrence and metastasis.

Figure 4. Schematic diagram of v-NKT cell function

Moreover, in the tumor microenvironment, an increase in the number of MDSCs (immunosuppressive cells) can produce arginase, TGF - β, NO, or IL-10, thereby inhibiting anti-tumor immune responses. V-NKT cells can also kill these MDSCs with immunosuppressive effects, achieving the effect of improving the anti-tumor microenvironment and eliminating tumors^[3]. Therefore, vNKT cell reinfusion provides a new treatment strategy for tumor patients who may have micro metastasis or have already undergone metastasis, which not only treats and prevents diseases but also has no side effects!

Immunotherapy for tumors has become a powerful tool in the fight against cancer, and the therapeutic effect of adoptive cell immunotherapy has become increasingly clear. At the same time, the body has a higher tolerance to these immunotherapy methods than traditional chemotherapy drugs. Of course, solid basic research is the key to the clinical application of tumor cell immunotherapy. The continuous expansion and exploration of indications for tumor cell immunotherapy are driving the rapid development of the clinical tumor cell immunotherapy field, and we look forward to achieving the ultimate goal of persistent cure for metastatic cancer!