MICA: key regulatory molecule for tumor immune surveillance and its therapeutic target potential

2. Mechanism of action and signaling pathways of MICA

2.1 Expression regulation and shedding mechanism of MICA

The expression of MICA is regulated by cellular stress signals, such as DNA damage, oxidative stress, or malignant transformation. In tumor cells, genomic instability often leads to transcriptional activation of the MICA gene, resulting in high surface expression ^[7,8]. However, tumor cells can cleave the MICA molecule by proteolysis, causing it to detach from the cell surface to form soluble MICA (sMICA). Studies have shown that metalloproteinases such as ADAM10 and ADAM17 are involved in this process, with cleavage sites located in the α3 domain of MICA ^[2,8]. sMICA not only reduces the density of NKG2D ligands on the surface of tumor cells, but also binds to circulating NKG2D, leading to receptor internalization and degradation, thereby weakening the antitumor activity of NK cells and T cells ^[4,8].

2.2 NKG2D-MICA signaling pathway

The signaling pathway initiated by the binding of NKG2D to MICA is mainly dependent on the adaptor protein DAP10 (DNAX-Activating Protein of 10 kDa). DAP10 contains an ITAM (Immunoreceptor Tyrosine-Based Activation Motif)-like motif that, after binding to NKG2D, activates downstream MAPK (Mitogen-Activated Protein Kinase) and MAPK (Mitogen-Activated Protein Kinase) by recruiting PI3K (Phosphatidylinositol 3-Kinase) and Akt kinase The NF-κB (Nuclear Factor kappa-B) signaling pathway ultimately promotes the release of cytotoxic molecules (e.g., perforin, granzyme) and the secretion of cytokines (e.g., IFN-γ) ^[3,4].

In NK cells, the balance of this signaling pathway with inhibitory receptors such as KIRs determines the activation status of NK cells. When MICA is highly expressed and inhibitory signals are weak, NK cells are fully activated to exert antitumor effects ^[8]. In the tumor microenvironment, the accumulation of sMICA can competitively bind to NKG2D, disrupting this signaling pathway and leading to immune escape ^[2,8].

3. MICA-related diseases

3.1 Malignant tumors

● Breast cancer: In triple-negative breast cancer (TNBC), the expression levels of MICA and MICB were positively correlated with NK cell infiltration. Elevated serum levels of sMICA in TNBC patients have been found to be associated with poor prognosis, and miR-486-5p can enhance NK cell killing of tumor cells by targeting MICA expression ^[7,9].

● Kidney cancer and melanoma: high expression of MICA on the surface of kidney cancer cells can be a target for NK cell attack, but tumor cells evade immune surveillance by shedding MCA. In melanoma, MICA expression is strongly associated with tumor progression and metastasis ^[8,10].

● Other tumors: MICA is aberrantly expressed in a variety of solid tumors, such as colorectal, ovarian, and pancreatic cancers, and its shedding levels can be used as biomarkers to assess tumor progression and prognosis ^[1,2].

3.2 Organ transplant rejection

Kidney transplant studies have shown that MICA mismatches between donors and recipients are significantly associated with reduced survival of transplanted kidneys. Patients with preoperative anti-MICA donor-specific antibodies (DSAs) have a significantly increased incidence of postoperative antibody-mediated rejection (ABMR), while new postoperative anti-MICA DSAs are associated with an increased risk of transplanted kidney failure ^[2,6]. In addition, there is a synergistic effect between MICA antibodies and HLA antibodies in transplant rejection, and the risk of ABMR is significantly increased when the two are co-existing ^[6].

4. Advances in drug research based on MICA targets

In February 2025, the mRNA vaccine mCM10-L, which targets the MICA/B α3 epitope, developed by a team from Zhejiang University, was published in Cell Reports Medicine, which significantly inhibits a variety of tumor metastasis by blocking MICA/B α1/2 shedding to activate immune cells ^[11]. At the same time, a number of MICA targeted drugs are in the preclinical or clinical research stage, with solid tumors as the main indication. Some of the pipelines under development are listed in the following table:

5. CUSABIO related product recommendation

● MICA recombinant protein

Recombinant Human MHC Class I chain-related protein (MICA), partial (Active); CSB-MP5605HU

Recombinant Human MHC Class I chain-related protein (MICA), partial (Active); CSB-MP5606HU

● MICA antibodies

MICA Recombinant Monoclonal Antibody; CSB-RA574653A0HU

MICA Antibody; CSB-PA013806ESR2HU

● MICB ELISA kit

Human major histocompatibility complex class I chain-related gene A (MICA) ELISA Kit

CSB-E13782h