Targeting the MICA/B-NKG2D axis in cancer: from molecular structure to immunotherapeutic strategies—a narrative review

Introduction

“Immune escape” was a hallmark of cancer, describing the process by which tumor cells evade recognition and destruction by the immune system, ultimately leading to metastatic outgrowth (1,2). This process was central to the cancer immunoediting paradigm, which comprises three phases: elimination, equilibrium, and escape (3,4). In the elimination phase, immune cells successfully eradicate developing tumors. However, this immune pressure can select for resistant tumor cell variants that enter an equilibrium phase and eventually emerge in the escape phase, where they grow into clinically apparent cancers (3,5). Recent advancements have further refined this model, proposing a “three Cs” framework—camouflage, coercion, and cytoprotection—to describe how immunologically sculpted tumors establish a profoundly suppressive microenvironment (2). Understanding the molecular mechanisms that drive this transition from elimination to escape was therefore critical for developing effective, personalized immunotherapies (6).

While tumor immunoediting was governed by multiple immune pathways, the major histocompatibility complex class I chain-related proteins A and B (MICA/B)-natural killer group 2 member D (NKG2D) axis plays a significant role in shaping early immune recognition and elimination of transformed cells (2,4,6). NKG2D was an activating receptor expressed on the surface of natural killer (NK) cells, CD8⁺ αβ T cells, and γδ T cells (5,7). Engagement of NKG2D by its ligands triggers a potent cytolytic response against target cells, orchestrating a critical bridge between innate and adaptive immunity (8). Under homeostatic conditions, MICA/B expression was largely restricted to intestinal epithelial cells, but they were potently upregulated on the surface of various epithelial-derived malignancies and stressed cells in response to DNA damage, heat shock, and viral infection (9-11). This selective expression positions MICA/B as powerful “danger signals” that flag abnormal cells for immune-mediated elimination, making them a key component of the elimination phase within the broader context of tissue-wide stress surveillance (12).

Given their potent immunostimulatory capacity, the MICA/B-NKG2D axis acts as a critical barrier to tumor development. However, as tumors evolve under immune pressure during the equilibrium phase (3), they acquire sophisticated mechanisms to disrupt this pathway—a defining feature of the escape phase (2). These mechanisms were remarkably diverse, ranging from transcriptional downregulation of MICA/B and their retention within intracellular compartments to, most notably, their proteolytic cleavage from the cell surface to generate soluble MICA/B (sMICA/B) (13,14). Critically, sMICA/B not only loses its ability to activate immune cells but also actively induces the internalization and degradation of NKG2D on effector cells, leading to profound and systemic immune suppression (15,16). This dual effect—loss of activating signal coupled with active receptor downregulation—makes shedding one of the most potent immune evasion strategies employed by tumors (17).

In this review, we trace the journey of MICA/B from its molecular architecture to its dysregulation in cancer and its emergence as a promising therapeutic target. We begin with an in-depth analysis of the structural determinants of MICA/B-NKG2D interaction, followed by a synthesis of the multi-layered regulatory mechanisms controlling MICA/B expression. We then explore how the tumor microenvironment (TME) shapes MICA/B biology and critically evaluate current and emerging therapeutic strategies aimed at restoring this critical axis. By integrating these perspectives, we aim to provide a comprehensive framework for understanding and therapeutically targeting the MICA/B-NKG2D pathway in cancer. We present this article in accordance with the Narrative Review reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1-2700/rc).

Methods

We conducted a structured literature search in PubMed for publications from database inception to March 2026. The search focused on studies addressing the molecular structure, polymorphism, expression regulation, proteolytic shedding, soluble ligand-mediated immunosuppression, tumor microenvironmental modulation, clinical relevance, and therapeutic targeting of the MICA/B-NKG2D axis in cancer. The main search terms included “MICA”, “MICB”, “NKG2D”, “NKG2D ligand”, “sMICA”, “sMICB”, “tumor immune escape”, “tumor microenvironment”, “natural killer cell”, “CD8+ T cell”, “immunotherapy”, “anti-MICA antibody”. Original experimental studies, clinical studies, translational studies, and selected high-quality reviews were considered. Studies were included when they provided relevant information on: (I) the molecular structure or polymorphism of MICA/B and their interaction with NKG2D; (II) transcriptional, epigenetic, post-translational, or microenvironmental regulation of MICA/B expression; (III) mechanisms and clinical implications of soluble MICA/B-mediated immune suppression; (IV) therapeutic strategies aimed at restoring or targeting the MICA/B-NKG2D axis. Studies were excluded if they were not directly related to MICA/B, NKG2D, cancer immunity, or immunotherapy; if the full text was unavailable; or if they were not published in English. The initial literature collection was performed by B.C. and C.G. Y.Z. and W.D. reviewed the selected articles and refined the literature according to the main thematic sections of the review. Disagreements regarding article inclusion or interpretation were resolved through discussion with X.L. Reference lists of relevant articles were also manually screened to identify additional landmark or recently published studies. Priority was given to recent publications from the past five years, whereas classic structural and mechanistic studies were retained when necessary to explain the biological basis of the MICA/B-NKG2D pathway. A detailed summary of the search strategy is provided in Table 1.

The molecular structure of MICA/B and its interaction with NKG2D

The MICA/B genes were highly polymorphic, located on the short arm of chromosome 6 (6p21.33) within the major histocompatibility complex (MHC) class I region (18). As of early 2026, over 600 MICA and 200 MICB alleles have been identified according to the international immunogenetics/human leukocyte antigen (IMGT/HLA) database, reflecting the intense evolutionary pressure on these ligands to respond to a broad spectrum of pathogens and cellular stressors (19,20). Despite this extensive genetic polymorphism, the core tertiary protein structure remains highly conserved to ensure stable recognition by the NKG2D receptor (Figure 1) (21).

Figure 1 Analysis of structural differences between MICA/B and classical MHC-I molecules, NKG2D binding interface, and polymorphism of MICA*008. (A) Structural comparison of classical MHC-I and MICA/B molecules. (B) MICA-NKG2D binding interface. (C) Polymorphism and structural differences between wild-type MICA/B and MICA008 variant. β2m, β2-microglobulin; GPI, glycosylphosphatidylinositol; KD, dissociation constant; MICA, major histocompatibility complex class I chain-related proteins A; MICA*008, MICA allele 008; MICB, major histocompatibility complex class I chain-related proteins B; MHC-I, major histocompatibility complex class I; NKG2D, natural killer group 2 member D; μM, micromolar. Created in BioRender.Li,X. (2026) https://BioRender.com/jigo2fd.

Domain architecture and crystal structure

MICA/B were type I transmembrane glycoproteins with a molecular weight of approximately 50 kDa (22). Their extracellular region comprises three domains: α1, α2, and α3, which were structurally homologous to the domains of classical MHC class I molecules (23). However, a critical distinction was that MICA/B do not associate with β2-microglobulin and lack a functional peptide-binding groove, thereby preventing the presentation of antigenic peptides (24,25). The ligand-binding site for the NKG2D receptor was specifically formed by the membrane-distal α1-α2 platform domain, which provides a symmetrical surface for receptor docking (21).

The crystal structure of the MICA-NKG2D complex has been solved, revealing the molecular basis for this high-affinity interaction (21). The interaction was mediated by a network of conserved residues within the α1-α2 domains of MICA that contact both NKG2D monomers, forming a stable and specific receptor-ligand complex (21). The affinity of the MICA-NKG2D interaction was in the micromolar range, consistent with a moderate-affinity receptor-ligand interaction that relies on multivalent engagement for effective signaling (21).

Structural distinctions between MICA and MICB and the role of polymorphism

Despite approximately 85% sequence identity, structural differences between MICA and MICB were primarily confined to variations in amino acid composition within the α1-α2 domains, leading to changes in surface topology and electrostatic properties that can modulate NKG2D binding affinity (26). In addition, MICA exhibits greater polymorphic diversity than MICB, contributing to increased structural heterogeneity at the receptor-binding interface (21,27). Accumulating evidence indicates that polymorphic variants can significantly alter surface expression and NKG2D engagement, thereby influencing immune activation thresholds.

The high degree of polymorphism in MICA/B has significant functional consequences. Polymorphic residues, often located in the α1-α2 domains, can alter binding affinity to NKG2D, potentially modulating the strength of the immune response (28,29). For instance, the common MICA*008 allele encodes a protein that lacks a traditional transmembrane domain and was instead glycosylphosphatidylinositol (GPI)-anchored protein (30). This variant was preferentially sorted to the apical membrane of epithelial cells and may be more susceptible to shedding, linking this polymorphism to differential immune evasion capabilities. Understanding these structural and polymorphic nuances was essential for designing effective immunotherapies that can target diverse patient populations (28,31).

Regulation of MICA/B expression: a multi-layered network

The expression of MICA/B on the cell surface was the central determinant of NKG2D-mediated immune recognition. This expression was governed by a complex, multi-layered regulatory network that cancer cells hijack to promote immune escape (Figure 2).

Figure 2 Regulatory pathways of MICA/B molecules at transcriptional, epigenetic and post-translational levels. ADAM10/17, a disintegrin and metalloproteinase 10/17; ADAMs, a disintegrin and metalloproteinases; BCL11B, B-cell leukemia/lymphoma 11B; CpG, cytosine-phosphate-guanine; GATA2/3, GATA binding protein 2/3; HDAC, histone deacetylase; HIF-1α, hypoxia-inducible factor 1α; MICA/B, major histocompatibility complex class I chain-related proteins A and B; MITF, microphthalmia-associated transcription factor; MMPs, matrix metalloproteinases; p53, tumor protein p53; sMICA/B, soluble MICA/B; TIMP3, tissue inhibitor of metalloproteinases 3. Created in BioRender.Li,X. (2026) https://BioRender.com/0cqhepd.

Transcriptional and epigenetic control

MICA/B transcription was primarily driven by stress-induced pathways, including the heat shock response and DNA damage response (32). Several transcription factors bind to promoter regions to regulate their expression. For example, GATA-binding protein 2/3 (GATA2/3) can be co-opted by viruses like hepatitis B virus (HBV) to suppress MICA/B in hepatocellular carcinoma (33). The tumor suppressor p53 can also directly activate MICA/B transcription in response to oncogenic stress (32).

Epigenetic mechanisms add another layer of complexity. Hypermethylation of promoter cytosine-phosphate-guanine (CpG) islands can silence MICA/B expression. Conversely, treatment with histone deacetylase inhibitors (HDACis) like valproic acid and entinostat potently upregulates MICA/B transcription by promoting an open chromatin state (34). Non-coding RNAs were also key regulators. For example, miR-20a, often overexpressed in ovarian and breast cancers, directly targets MICA/B mRNA, reducing surface expression and dampening NK cell cytotoxicity (35). Interestingly, as Qian et al. demonstrated, the long non-coding RNA B-cell leukemia/lymphoma 11B (BCL11B) can act as a competing endogenous RNA (ceRNA) to sponge such microRNAs, thereby upregulating MICA/B and blocking immune escape (36,37). This illustrates the delicate balance of epigenetic control. In summary, transcriptional and epigenetic regulation serves as a primary gatekeeper of MICA/B expression, and its disruption was a fundamental step in tumor immune evasion.

Post-translational regulation: the central role of proteolytic shedding

The most extensively studied mechanism of MICA/B dysregulation was their proteolytic shedding from the tumor cell surface. This process was carried out by members of the a disintegrin and metalloproteinases (ADAMs) family and matrix metalloproteinases (MMPs) (38). A disintegrin and metalloproteinase 10 (ADAM10) and a disintegrin and metalloproteinase 17 (ADAM17) were the main shedding enzymes of MICA/B. They cleave these proteins at the proximal part of the membrane to release the extracellular domains (39,40).

Numerous tumor-intrinsic and microenvironmental factors promote this shedding. For instance, hypoxia-induced factor 1-alpha (HIF-1α) upregulates ADAM10, leading to increased MICA/B shedding in pancreatic cancer (41). Similarly, the microphthalmia-associated transcription factor (MITF) in melanoma promotes ADAM10 expression, facilitating immune evasion (42). In addition to ADAM10, ADAM17 also plays a critical role in MICA/B shedding. For example, estradiol has been shown to enhance ADAM17 expression in non-small cell lung cancer cells, thereby promoting the proteolytic release of MICA/B and impairing NK cell-mediated cytotoxicity (43). Beyond direct transcriptional control, the activity of these sheddases was itself regulated. The tissue inhibitor of metalloproteinases 3 (TIMP3) was a natural inhibitor of ADAMs and MMPs. Hypermethylation of the TIMP3 promoter, often seen in tumors, leads to its silencing and consequently, unchecked MICA/B shedding (44).

In summary, the proteolytic shedding of MICA/B mediated by ADAM10 and ADAM17 represents a critical immune evasion mechanism exploited by tumors. This process is driven by a complex interplay of tumor-intrinsic factors, microenvironmental cues, and epigenetic silencing of the natural inhibitor TIMP3, highlighting multiple layers of regulation that facilitate immune escape.

Mechanisms and clinical implications of sMICA/B-mediated immunosuppression

While loss of surface MICA/B prevents immune activation, the generation of sMICA/B exerts its own profound and dominant immunosuppressive effects through distinct molecular mechanisms that operate at the receptor, cellular, and clinical levels (Figure 3) (12,45,46).

Figure 3 Mechanisms of sMICA/B-mediated NKG2D pathway immunosuppression and tumor microenvironment synergy. CD3ζ, CD3 zeta chain; CD8⁺ T cell, CD8-positive T cell; DAP10, DNAX-activating protein 10; IFN-γ, interferon-gamma; IL-15, interleukin-15; MICA/B, major histocompatibility complex class I chain-related proteins A and B; NK cell, natural killer cell; NKG2D, natural killer group 2 member D; NKp30/46, natural killer p30/46; PI3K, phosphatidylinositol 3-kinase; sMICA/B, soluble MICA/B; TCR, T cell receptor; TGF-β, transforming growth factor-beta; TME, tumor microenvironment; Ub, ubiquitin. Created in BioRender.Li,X. (2026) https://BioRender.com/hh5fju4.

Receptor downregulation and lysosomal degradation

sMICA/B retains the ability to bind NKG2D, although the functional outcomes differ due to reduced avidity and the lack of multivalent engagement compared to its membrane-bound counterpart (47). The membrane-bound MICA/B forms multivalent interactions that promote receptor clustering and sustained signaling at the immunological synapse, whereas sMICA/B engages NKG2D in a monomeric or low-avidity manner, which can impair receptor activation and promote immune evasion (11,48). This monomeric engagement fails to induce stable clustering of NKG2D required for efficient phosphorylation of the adaptor molecule DNAX-activation protein 10 (DAP10) and subsequent activation of downstream phosphoinositide 3-kinase (PI3K) signaling pathways, ultimately impairing cytotoxic responses of effector cells (11,49).

Upon binding, the sMICA/B-NKG2D complex was rapidly internalized via clathrin-mediated endocytosis (50,51). This process was driven by constitutive cycling of NKG2D between the cell surface and intracellular compartments; sMICA/B engagement biases this equilibrium toward internalization (52). The internalized receptor was targeted for lysosomal degradation through ubiquitination of its cytoplasmic tail, which tags the receptor for sorting into multivesicular bodies (53). The result was a sustained loss of surface NKG2D expression that persists even after sMICA/B clearance, rendering effector cells functionally “blind” to MICA/B-expressing tumor targets (54).

Functional exhaustion of effector cells

Chronic exposure to sMICA/B induces a state of NK cell exhaustion characterized by impaired interferon-gamma (IFN-γ) production, reduced cytolytic granule release, and downregulation of other activating receptors including natural killer cell p30-related protein (NKp30) and natural killer cell p46-related protein (NKp46) (55,56). In CD8+ T cells, sMICA/B binding additionally destabilizes CD3ζ within the T-cell receptor (TCR) complex, impairing antigen-specific recognition (15). These functional defects are further amplified in the immunosuppressive TME. The transforming growth factor-beta (TGF-β) cooperates with sMICA/B to reduce NKG2D expression, impairing tumor recognition, while also disrupting interleukin-15 (IL-15)-dependent metabolic support, ultimately weakening the cytotoxic activity of effector cells (55,57).

Clinical relevance as a prognostic biomarker

Elevated sMICA/B levels were detected in sera of patients with a wide variety of cancers, including melanoma, pancreatic, lung, colorectal, and ovarian cancers (58,59). Numerous studies have correlated high serum sMICA/B levels with advanced disease stage, metastasis, reduced NKG2D expression on circulating NK cells, and poor patient prognosis (59,60). sMICA/B therefore serves a dual role—as a mechanistic driver of immune escape and as a valuable, non-invasive prognostic biomarker. This clinical correlation provides the rationale for therapeutic strategies aimed at inhibiting MICA/B shedding (59,61).

Regulation of MICA/B in the TME

TME was a dynamic ecosystem composed of malignant cells, stromal cells [cancer-associated fibroblasts (CAFs)], immune infiltrates [macrophages, myeloid-derived suppressor cells (MDSCs)], and extracellular matrix components (62). Beyond tumor-intrinsic mechanisms, the TME dynamically regulates MICA/B expression and function through cytokine signaling, metabolic stress, and intercellular interactions, collectively contributing to NKG2D dysfunction and immune evasion (Figure 4) (62).

Figure 4 Three-layered molecular pathway of tumor microenvironment and metabolic stress regulating MICA/B-mediated immune evasion. ADAM10, a disintegrin and metalloproteinase 10; CAF, cancer-associated fibroblast; CD8⁺ T cell, CD8-positive T cell; ER, endoplasmic reticulum; HIF-1α, hypoxia-inducible factor 1α; IL-10, interleukin-10; IL-1β, interleukin-1 beta; IL-6, interleukin-6; MDSC, myeloid-derived suppressor cell; MICA/B, major histocompatibility complex class I chain-related proteins A and B; MMPs, matrix metalloproteinases; NK cell, natural killer cell; NKG2D, natural killer group 2 member D; PROS1-AXL, protein S-AXL receptor tyrosine kinase; STAT3, signal transducer and activator of transcription 3; TAM, tumor-associated macrophage; TGF-β, transforming growth factor-beta; TNF-α, tumor necrosis factor-alpha. Created in BioRender.Li,X. (2026) https://BioRender.com/fpoc80o.

CAFs

CAFs were key players in TME-driven immune suppression. As highlighted by Ziani et al., CAFs secrete MMPs that cleave MICA/B directly from the surface of adjacent melanoma cells, reducing their susceptibility to NK cell killing (63). This paracrine shedding operates independently of the tumor cell’s own shedding machinery, underscoring how stromal elements can dominantly disable the NKG2D ligand axis. Previous studies have shown that CAFs may further downregulate the transcriptional levels of MICA/B genes in cancer cells through TGF-β (64,65).

Tumor-associated macrophages (TAMs)

TAMs were increasingly recognized as critical regulators of the MICA/B-NKG2D axis within the TME. Accumulating evidence indicates that tumor-derived sMICA/B, generated through proteolytic shedding, can impair antitumor immunity by downregulating NKG2D expression and function on cytotoxic lymphocytes (66). Notably, recent studies have demonstrated that MICA-expressing tumor cells can actively engage macrophages and induce the secretion of MMPs such as matrix metalloproteinase 9 (MMP9) via the protein S-AXL receptor tyrosine kinase (PROS1-AXL) signaling axis, thereby promoting MICA shedding and facilitating immune escape (38). In parallel, sMICA/B has been shown to modulate immune cell signaling pathways, including signal transducer and activator of transcription 3 (STAT3), contributing to immunosuppressive reprogramming within the TME (66). Conversely, TAMs can act upstream to regulate MICA/B expression through cytokine-mediated mechanisms. Macrophage-derived inflammatory cytokines, including tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6), have been reported to modulate MICA/B transcription via pathways such as janus kinase (JAK)/STAT3 and PI3K/protein kinase B (AKT) (67), highlighting the bidirectional crosstalk between macrophages and tumor cells.

MDSCs

Within the TME, MDSCs were functionally linked to the MICA/B-NKG2D axis, primarily through interactions with soluble forms of these ligands. Tumor-derived sMICA/B, generated via proteolytic shedding, not only impair cytotoxic lymphocyte activity but also actively contribute to the expansion and functional reprogramming of MDSCs. In particular, soluble MIC has been shown to promote the accumulation of MDSCs and enhance their immunosuppressive activity through activation of STAT3 signaling pathways (68). Consistently, elevated levels of sMICA/B in tumors were associated with enhanced MDSC expansion and suppression of antitumor immunity (69). In turn, expanded MDSCs produce high levels of immunosuppressive mediators, including TGF-β and interleukin-10 (IL-10), and contribute to the downregulation and functional impairment of NKG2D on NK cells and CD8⁺ T cells.

Extracellular vesicles (EVs) and exosomes

EVs, particularly exosomes, have emerged as important mediators of intercellular communication within the TME and play a significant role in modulating the MICA/B-NKG2D axis (70). Numerous studies have confirmed that exosomes bear full-length MICA/B on their surface, effectively acting as decoys that bind NKG2D on effector cells, leading to receptor downregulation and functional exhaustion (71,72). A recent study revealed that hypoxic tumor cells release exosomes enriched in MICA/B, and these exosomes also contain TGF-β, which further suppresses NK cell activity (73). Collectively, these findings suggest that EV-mediated trafficking of MICA/B represents an additional layer of immune evasion, complementing proteolytic shedding and contributing to the functional exhaustion of the NKG2D-dependent antitumor response.

Metabolic regulation

Metabolic reprogramming within the TME represents an important layer of regulation of the MICA/B-NKG2D axis. Tumor-associated metabolic stressors, including hypoxia, nutrient deprivation, and lactate accumulation, have been shown to influence both the expression and functional availability of NKG2D ligands. Hypoxia, largely mediated by HIF-1α, can promote the shedding of MICA/B through upregulation of metalloproteinases such as ADAM10, thereby reducing their surface expression on tumor cells (41,74). In additional, glucose deprivation, a common feature of the TME, can impair N-linked glycosylation of MICA/B, leading to their misfolding and retention in the endoplasmic reticulum (75,76). In parallel, metabolic byproducts such as lactate contribute to an immunosuppressive milieu that impairs NKG2D expression and function on NK cells and CD8⁺ T cells (77). Collectively, these metabolic constraints diminish effective immune recognition while enhancing ligand release, suggesting that metabolic stress cooperates with proteolytic mechanisms to promote tumor immune evasion.

Concluding remarks on TME-driven MICA/B regulation

Collectively, the TME orchestrates a multifaceted assault on the MICA/B-NKG2D axis. Stromal and immune cells contribute paracrine sheddases, suppressive cytokines, and regulatory vesicles, while metabolic constraints and hypoxia further erode ligand expression and function. These TME-driven mechanisms operate in concert with tumor-intrinsic alterations and the selective pressures of immunoediting, creating a formidable barrier to NKG2D-mediated immunity. Therapeutic strategies that fail to account for this complexity—for instance, by targeting only tumor-intrinsic shedding while ignoring paracrine shedding from CAFs or exosome-mediated decoy effects—were unlikely to achieve durable responses. Effective next-generation approaches must therefore be designed to counteract the full spectrum of TME-driven immune evasion.

Targeting the MICA/B-NKG2D axis: therapeutic strategies and challenges

The recognition that MICA/B dysfunction was a central mechanism of tumor immune escape has galvanized the development of diverse therapeutic strategies aimed at restoring this critical axis. As summarized in Table 2, these approaches can be categorized into four mechanistically distinct classes based on their mode of action: inhibitors of MICA/B shedding, enhancers of MICA/B expression, MICA/B-directed cellular therapies, and rationally designed combination strategies.

Inhibitors of MICA/B shedding

The most direct approach to restore MICA/B function is to block its proteolytic cleavage by ADAMs and MMPs from the tumor cell surface. Monoclonal antibodies targeting the MICA/B stalk region represent the most clinically advanced class. The prototypic antibody 7C6 binds to the α3 domain, physically occluding access to ADAM proteases while engaging fragment crystallizable gamma (Fcγ) receptors on NK cells and macrophages to induce antibody-dependent cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) (78,104). CLN-619 was the first agent in this class to enter phase 1 clinical trials, evaluating monotherapy and combination with pembrolizumab in advanced solid tumors. Preliminary results demonstrated favorable safety profiles and early signals of clinical activity, including responses in tumor types typically resistant to checkpoint inhibitors alone (79). AHA-1031, a novel ADCC-enhanced MICA/B antibody engineered with an immunoglobulin G1 (IgG1) Fc domain, has demonstrated potent monotherapy activity in kirsten rat sarcoma viral oncogene homolog (KRAS)/liver kinase B1 (LKB1) mutant non-small cell lung cancer models—a subtype notoriously resistant to immune checkpoint blockade—by stabilizing MICA/B and promoting NK cell infiltration (80).

Translational challenges for shedding inhibitors include: (I) extreme polymorphism of MICA/B, which may limit antibody coverage across diverse alleles (81); (II) high baseline sMICA/B levels that could act as a therapeutic antibody “sink” (105); and (III) on-target off-tumor toxicity concerns due to MICA/B expression on healthy stressed tissues (50). Broad inhibition of ADAM metalloproteases has been explored as a strategy to block MICA/B shedding; however, the lack of substrate specificity and potential off-target toxicity have limited the clinical translation of these small-molecule inhibitors; alternative indirect approaches aim to enhance endogenous metalloprotease inhibitors such as tissue inhibitor of metalloproteinase 3 (TIMP3), for example through fatty acid amide hydrolase (FAAH) inhibition (e.g., URB597) or epigenetic modulation using hypomethylating agents (44,82,83).

Enhancers of MICA/B expression

A complementary strategy involves increasing MICA/B density on tumor cells through transcriptional or epigenetic modulation. HDACis were the most extensively studied class, with entinostat, sodium butyrate, and valproic acid upregulating MICA/B transcription across multiple cancer types through chromatin remodeling (84-87). In myeloma cells, valproic acid acts via the extracellular regulated protein kinases (ERK) signaling pathway to enhance NK cell sensitivity (88).

Beyond HDACis, a range of signal transduction modulators target diverse regulatory nodes that converge on MICA/B expression. The oncogenic transcription factor cellular myelocytomatosis (c-Myc) has been reported to repress MICA/B expression through activation of the miR-17-92 microRNA cluster. Accordingly, pharmacologic agents such as resveratrol can relieve this repression by inhibiting the c-Myc/miR-17 signaling axis, thereby restoring MICA/B expression and enhancing NK-cell-mediated cytotoxicity in breast cancer cells (89,90). In hepatocellular carcinoma, the p38/mitogen-activated protein kinase (MAPK) signaling pathway has emerged as a positive regulator of MICA/B expression; for instance, an anterior gradient-2 (AGR2)-derived peptide has been shown to enhance MICA/B expression through activation of this pathway, thereby promoting immune recognition by NK cells (91). Viral mimicry represents another strategy to enhance tumor immunogenicity. Polyinosinic-polycytidylic acid (poly I:C), a synthetic double-stranded RNA analog, activates innate immune sensors such as Toll-like receptor 3 and has been shown to upregulate both MICA/B and CD95 (Fas) expression in gastric cancer cells, thereby increasing their susceptibility to immune-mediated killing (92).

Despite these promising strategies, translational challenges remain. In particular, epigenetic modulators such as HDACis often exhibit pleiotropic effects and may simultaneously induce immunosuppressive molecules, underscoring the need for careful optimization of dosing strategies and rational combination therapies to maximize antitumor immunity while minimizing unintended immune suppression.

MICA/B-directed cellular therapies

Engineering immune cells to recognize MICA/B-positive tumors represents a promising strategy that bypasses the need for tumor-specific antigens and exploits stress-induced ligands broadly expressed across malignancies. Chimeric antigen receptor (CAR) T cells and CAR-NK cells targeting NKG2D ligands, including MICA and MICB, are currently under active investigation. One of the earliest designs utilized an NKG2D-based CAR capable of recognizing multiple NKG2D ligands expressed on tumor cells, enabling targeting of diverse solid tumors (93,94).

The NKG2D-based CAR-T product CYAD-2 was found to have paradigm-shifting significance during its clinical development process. In this construct, shRNA-mediated knockdown of NKG2D ligands within the CAR-T cells themselves was introduced to prevent fratricide and enhance CAR-T cell persistence. Early-phase clinical studies reported encouraging activity in relapsed or refractory acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), demonstrating the feasibility of targeting stress-induced ligands while mitigating self-recognition by engineered T cells (95).

Another NKG2D-based CAR-T therapy, CYAD-01, has also entered clinical evaluation and represents one of the first cellular therapies designed to target multiple NKG2D ligands, including MICA/B, UL16-binding protein (ULBP) family proteins, and other stress-induced molecules. Early clinical trials have demonstrated acceptable safety profiles and preliminary antitumor activity in patients with advanced solid tumors and hematologic malignancies, highlighting the therapeutic potential of targeting stress-induced immune ligands (96).

Complementing CAR-based strategies, emerging approaches aim to reprogram immune effector cells with enhanced innate tumor recognition. For example, depletion of the transcription factor BCL11B has been shown to reprogram peripheral blood mononuclear cells into functional NK-like cells with elevated NKG2D expression and enhanced cytotoxicity. When combined with protein kinase membrane associated tyrosine/threonine 1 (PKMYT1) inhibition—which increases tumor-cell MICA/B expression—this strategy achieved synergistic antitumor effects in pancreatic ductal adenocarcinoma models, illustrating a “NK reprogramming plus drug sensitization” therapeutic paradigm (97).

Furthermore, broader lessons from CAR-T resistance research suggest that modulation of intracellular trafficking pathways and receptor recycling may influence CAR signaling persistence and antigen engagement. These insights may inform future optimization of MICA/B-directed cellular therapies to improve durability of response and limit antigen escape (106).

Combination strategies and therapeutic synthesis

Given the redundancy of tumor immune evasion mechanisms, combining MICA/B-targeted agents with other immunotherapies is likely essential for achieving durable antitumor responses. Anti-shedding antibodies combined with immune checkpoint inhibitors represent a particularly rational strategy. Restoration of membrane-bound MICA/B can increase tumor immunogenicity and enhance NK- and T-cell activation, potentially sensitizing tumors to programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) blockade. This rationale underlies ongoing clinical evaluation of anti-MICA/B antibodies such as CLN-619 in combination with pembrolizumab (80,98).

Similarly, pharmacologic priming strategies may further enhance immune recognition. HDACis can transcriptionally upregulate MICA/B expression through chromatin remodeling, thereby increasing tumor susceptibility to NK-cell-mediated cytotoxicity. Pre-treating tumors with HDACis prior to NK cell infusion has therefore been proposed as a strategy to enhance adoptive NK cell therapy (84,99).

Emerging evidence also indicates that tumors may develop adaptive resistance mechanisms in response to enhanced NKG2D signaling. For example, tumor cells can upregulate non-classical MHC molecules such as HLA-E, which engage the inhibitory receptor natural killer group 2 member A (NKG2A) on NK and CD8⁺ T cells. This observation provides a rationale for combining MICA/B-directed therapies with NKG2A blockade in order to simultaneously restore activating signals while relieving inhibitory pathways (100,101).

The strategies summarized in Table 1 can therefore be understood as complementary approaches that operate at different regulatory levels. Shedding inhibitors and transcriptional enhancers both aim to increase surface MICA/B density but act through distinct mechanisms—post-translational versus transcriptional/epigenetic regulation—suggesting potential therapeutic synergy. For example, HDACis may prime tumors by increasing MICA/B transcription, whereas anti-shedding antibodies stabilize these ligands on the cell surface and prolong their availability for immune recognition (84,102).

Cellular therapies represent a different strategy by bypassing endogenous ligand regulation altogether; however, these approaches must carefully balance therapeutic efficacy with potential on-target off-tumor toxicity due to MICA/B expression in stressed normal tissues (93). Finally, bispecific approaches are also emerging. The fusion protein mAb04-MICA, which simultaneously targets vascular endothelial growth factor receptor 2 (VEGFR2) while engaging NKG2D signaling pathways, exemplifies a strategy designed to integrate anti-angiogenic effects with immune activation (107). Ongoing clinical and translational studies will ultimately determine which combinations, treatment sequences, and patient populations derive the greatest benefit from these integrated therapeutic approaches.

Research challenges and future prospects

The MICA/B-NKG2D axis occupies a unique position at the interface of cellular stress surveillance and anti-tumor immunity. As synthesized in this review, the journey from ligand expression to immune activation—and its subversion in cancer—was governed by a complex network of regulatory mechanisms. At the molecular level, the high-affinity interaction between MICA/B and NKG2D was finely tuned by structural polymorphisms that vary across populations (103,108). At the cellular level, expression was controlled through transcriptional, epigenetic, and post-translational mechanisms, among which proteolytic shedding by ADAM10 and ADAM17 represents a dominant immune evasion strategy that generates immunosuppressive sMICA/B (109,110). Within the TME, stromal cells (CAFs, TAMs, MDSCs), metabolic stress, and EVs further contribute to suppression of this axis through paracrine shedding, post-translational modifications, and exosome-mediated decoy mechanisms (111). Together with the evolutionary pressure of immunoediting, these multilayered mechanisms help explain why MICA/B dysfunction is so prevalent across diverse cancer types.

The therapeutic landscape for targeting this axis has evolved rapidly, with the first MICA/B-targeted agents now entering early-phase clinical trials. Shedding inhibitors such as CLN-619 have demonstrated favorable safety profiles and early signals of clinical activity as monotherapy and in combination with PD-1 blockade (79). MICA/B-directed cell therapies have also advanced, with studies demonstrating that engineering NKG2D-based CAR-T cells to reduce fratricide can improve persistence and antitumor activity (112). Despite these promising developments, substantial challenges remain, including the extreme polymorphism of MICA/B, high baseline sMICA/B levels that may neutralize therapeutic antibodies, and concerns about on-target off-tumor toxicity. Emerging evidence of adaptive resistance mechanisms—such as tumor cells upregulating HLA-E in response to immune pressure—highlights the need for rationally designed combination strategies (100,113).

Looking forward, several priority areas warrant focused investigation. First, functional annotation of MICA/B polymorphisms through large-scale studies was essential to correlate specific alleles with therapy response and guide personalized approaches. Second, prospective validation of sMICA/B levels, tumor MICA/B expression, and genetic polymorphisms as predictive biomarkers was urgently needed for patient stratification. Third, deeper mechanistic understanding of TME-driven regulation will inform rational combination therapy design. Fourth, next-generation therapeutic engineering—including affinity-tuned CARs with controllable MICA/B expression and multispecific molecules that simultaneously engage NKG2D while blocking inhibitory pathways—may help mitigate toxicity while focusing immune responses.

Conclusions

In summary, the MICA/B-NKG2D axis stands as a paradigm of how a single receptor-ligand system can integrate stress surveillance, innate immunity, and adaptive immunity. Its frequent dysregulation in cancer underscores its gatekeeper function, while the recent clinical translation of MICA/B-targeted agents marks a pivotal step toward harnessing this axis therapeutically. Although substantial biological and translational hurdles remain, the convergence of mechanistic insights, innovative trial designs, and next-generation engineering positions this field for transformative impact. With sustained interdisciplinary effort, targeting the MICA/B-NKG2D pathway may ultimately expand the repertoire of effective immunotherapies and improve outcomes for patients who currently derive limited benefit from existing treatments.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1-2700/rc

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1-2700/prf

Funding: This study was supported by the Taizhou Science and Technology Program Project (No. 25ywb07).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1-2700/coif). The authors have no conflicts of interest to declare.

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