1. The S100 Protein Family and S100A8/S100A9: What Are They?

The S100 protein family consists of low-molecular-weight calcium-binding proteins widely found in vertebrates, initially discovered in nervous tissue. These proteins typically function by forming homodimers or heterodimers to exert biological activities. Each S100 protein monomer contains two EF-hand domains that bind calcium ions, playing a crucial role in calcium signaling. Upon calcium binding, the protein undergoes a conformational change, exposing interfaces for interaction with other proteins and participating in various cellular processes such as proliferation, differentiation, motility, and apoptosis.

As key members of this family, S100A8 and S100A9 often form a heterodimer (S100A8/A9), also known as calprotectin. The genes encoding these proteins are located in the human chromosomal region 1q21, which frequently exhibits abnormalities in various cancers, suggesting a potential close association with tumorigenesis. S100A8 and S100A9 are highly expressed in neutrophils, monocytes, and dendritic cells, with particularly high levels in neutrophil cytoplasm. In recent years, researchers have found that their expression is dysregulated in multiple cancers, implicating them not only in inflammation and immune regulation but also playing a critical role in tumor initiation, progression, and metastasis.

2. How Do S100A8/S100A9 Participate in the Process of "Nutritional Immunity"?

When pathogens such as bacteria invade the human body, immune cells release the S100A8/A9 heterodimer. This protein complex can chelate trace elements like Zn²⁺ and Mn²⁺, depriving pathogens of essential nutrients, thereby inhibiting microbial growth and promoting their death. This phenomenon is known as "nutritional immunity." For example, S100A8/A9 demonstrates significant antibacterial activity against infections such as Staphylococcus aureus and Helicobacter pylori. However, the specific mechanisms of its action against H. pylori require further investigation. Whether this mechanism indirectly affects immune responses in the tumor microenvironment is one of the current hot topics in research.

3. What Dual Roles Do S100A8/S100A9 Play in Inflammation?

Inflammation is closely related to cancer, and S100A8 and S100A9 exhibit dual roles in inflammatory processes. In the early stages of inflammation, they act as pro-inflammatory factors, activating signaling pathways such as NF-κB, enhancing leukocyte aggregation and migration, thereby amplifying the inflammatory response. However, as inflammation progresses, high concentrations of S100A8/A9 may shift to suppress excessive inflammation, reduce tissue oxidative damage, and promote repair processes. The dysregulation of this dynamic balance, particularly the sustained high expression of S100A8/A9 in chronic inflammation, provides a favorable microenvironment for tumors, accelerating the process of malignant transformation.

4. How Do S100A8/S100A9 Promote Tumor Initiation and Development?

The tumor microenvironment (TME) is crucial in cancer progression, and S100A8/A9 is considered a key molecule linking chronic inflammation to tumorigenesis. In various malignancies such as gastric cancer, breast cancer, and colorectal cancer, the expression of S100A8 and S100A9 is significantly upregulated. They interact with cell surface receptors (e.g., RAGE), activating downstream signaling pathways (e.g., MAPK and NF-κB), thereby promoting tumor cell proliferation, inhibiting apoptosis, and enhancing invasive and migratory capabilities.

Studies have shown that inhibiting the expression of S100A8 or S100A9 using RNA interference technology significantly reduces the migration and invasion abilities of tumor cells. Additionally, clinical data analysis has revealed that the expression level of S100A9 is negatively correlated with the TNM stage of gastric cancer but positively correlated with patient prognosis, suggesting its potential as a biomarker for assessing disease progression and outcomes.

5. What Potential Do S100A8/S100A9 Hold in Cancer Immunotherapy?

Tumor-associated immunosuppression is a major challenge in current cancer treatment. Myeloid-derived suppressor cells (MDSCs), as important immunosuppressive cells in the TME, highly express S100A8/A9 and suppress T-cell function through various mechanisms (e.g., depleting cysteine and releasing reactive oxygen species), thereby facilitating tumor immune escape.

Recent studies indicate that blocking S100A8/A9 or its receptors (e.g., RAGE or TLR4) can reverse the immunosuppressive function of MDSCs and restore T-cell anti-tumor activity. Consequently, targeting the S100A8/A9 signaling axis has become an important direction for developing novel immunotherapies. For example, strategies such as monoclonal antibodies against S100A8/A9, small molecule inhibitors, or combinations with existing immune checkpoint inhibitors are showing promise in preclinical and early clinical studies.

6. Summary and Outlook: What Is the Future of S100A8/S100A9 Research?

As multifunctional proteins, S100A8 and S100A9 play significant roles in infection, inflammation, and cancer. They not only participate in the competition for trace elements in innate immunity but also influence cancer initiation, progression, and immune escape by modulating inflammatory responses and the tumor microenvironment. Particularly noteworthy is their role in promoting the transformation from chronic inflammation to cancer, providing a molecular basis for understanding the "inflammation-cancer" transition.

Future research should focus more on exploring the specific mechanisms of S100A8/A9 in tumor immune regulation and developing corresponding targeted therapeutic strategies. High-throughput screening for compounds that inhibit S100A8/A9 function or designing combination therapies to enhance the efficacy of existing immunotherapies will be important research directions. Additionally, detecting S100A8/A9 levels in blood or tissue samples holds promise as a non-invasive biomarker for predicting cancer risk, monitoring treatment response, and assessing prognosis.

Through continued in-depth research, S100A8/S100A9 are not only expected to become new targets for cancer treatment but may also open new therapeutic avenues in tumor immunology.

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