Few molecules in immunology have traveled as remarkable a path from basic discovery to cancer biology as myeloid differentiation factor 88, better known as MyD88. First identified in the 1990s as a protein upregulated during interleukin-6-induced myeloid differentiation, MyD88 was subsequently revealed to be the canonical adaptor protein downstream of the Toll-like receptor (TLR) and interleukin-1 receptor families. In that capacity, it channels signals that activate the transcription factor NF-κB and allied pathways, driving the proliferation and survival of B cells and underpinning much of innate immunity. A new open-access review published in Clinical Cancer Bulletin by Jiahui Liu, Shipeng Zhu, and colleagues from Renmin Hospital of Wuhan University and Zhejiang University School of Medicine now synthesizes decades of evidence showing that this same signaling hub sits at the crossroads of tumor initiation and growth, in both blood cancers and solid malignancies.
The technical architecture of the MyD88 pathway explains why it carries such weight. Toll-like receptors are pattern recognition receptors that detect pathogen-associated molecular patterns and damage-associated molecular patterns. Humans possess ten TLRs and mice twelve, distributed between the cell membrane and intracellular organelles. Structurally, TLRs are type I transmembrane proteins with an extracellular leucine-rich domain, a transmembrane segment, and an intracellular Toll/IL-1 receptor (TIR) domain. When a ligand engages the receptor, the TIR domain changes conformation and recruits MyD88, whose own C-terminal TIR domain forms heterodimers with the receptor and homodimerizes with itself, a step considered critical for signal transduction. The sole exception is TLR3, which signals independently of MyD88 through the TRIF adaptor. MyD88’s N-terminal death domain then attracts the kinases IRAK1 and IRAK4; IRAK4 phosphorylates IRAK1, which activates TRAF6 and, in turn, the NF-κB, MAPK, and PI3K-Akt cascades.
Nowhere is the oncogenic potential of this pathway clearer than in hematologic malignancy. The missense mutation L265P, which swaps a leucine for a proline at position 265 of MyD88, is found in roughly 90 percent of cases of Waldenström’s macroglobulinemia (WM), as well as in a large proportion of activated diffuse large B-cell lymphoma and IgM monoclonal gammopathy of undetermined significance. The review emphasizes how unusual this is in cancer: a single amino acid change acting as a dominant driver of disease, making WM a paradigm for treating disorders caused by one genetic alteration. Mechanistically, the L265P mutation renders the TIR domain hyperactive, strengthening binding to IRAK4 and phosphorylated IRAK1 so that the myddosome complex assembles even without external stimuli. The result is constitutive NF-κB signaling that sustains the survival and proliferation of malignant B cells.
The mutation also rewires cooperating pathways. In WM cells carrying L265P, MyD88 complexes with phosphorylated Bruton’s tyrosine kinase (pBTK) within the B-cell receptor signaling cascade, and disrupting this complex triggers apoptosis. MyD88 additionally activates transcription of the hematopoietic cell kinase HCK through NF-κB, and reducing HCK diminishes WM cell survival. Phelan and colleagues identified a MyD88-TLR9-BCR super-complex that engages the mTOR and CBM complexes to promote lymphomagenesis. Downstream, the pathway triggers autocrine IL-6 and IL-10 signaling, which phosphorylates JAK1 and then STAT3; STAT3 enhances expression of NF-κB, PI3K-AKT-mTORC1, and cell cycle checkpoint genes while suppressing interferon signaling components such as IRF7, IRF9, STAT1, and STAT2. Notably, selective IRAK1 and IRAK4 inhibitors killed ABC-DLBCL cells but promoted survival in GCB-DLBCL and myeloma lines, underscoring the context dependence of pathway targeting.
These insights are already shaping therapy. Although no drug directly approved against MyD88 exists for WM, the current frontline agent is the BTK inhibitor ibrutinib, and patients with MyD88 mutations respond exceptionally well: nearly all, 97.2 percent, achieve a major response, a phenomenon the authors attribute to MyD88’s involvement in B-cell receptor signaling. Combining BTK and IRAK inhibition is a plausible future strategy, and the review suggests that MyD88 itself remains a significant therapeutic target under active investigation.
In solid tumors, the story stretches back to Rudolf Virchow’s nineteenth-century observation linking inflammation to tumor growth. Chronic inflammation promotes cancer by augmenting DNA damage, driving tissue remodeling, secreting growth factors, and enhancing angiogenesis, and MyD88 sits at the center of these processes through its role in inflammation and the tumor microenvironment. In colitis-associated colorectal cancer, work in APC(Min/+) mice showed that MyD88 phosphorylates c-Myc via the ERK pathway, preventing its ubiquitination and proteasomal degradation; mice lacking MyD88 developed fewer and smaller tumors. MyD88-deficient myofibroblasts rendered mice resistant to AOM/DSS-induced tumorigenesis, partly by preventing macrophage M2 polarization through STAT3 and PPARγ signaling, and MyD88 inhibitors have been shown to curb both local and systemic inflammation while suppressing ERK signaling in intestinal epithelial cells.
The liver offers a parallel narrative. Human hepatocellular carcinoma tissues express higher levels of MyD88 than normal liver, and the adaptor activates PI3K-Akt signaling and accelerates epithelial-mesenchymal transition, promoting proliferation and metastasis. Knocking down the chemokine receptor CXCR3 reduces MyD88 expression, inhibiting cell proliferation and migration and slowing progression from fibrosis to cancer, while silencing MyD88 with siRNA impedes tumor cell growth. MyD88 also promotes non-alcoholic fatty liver-related hepatocarcinogenesis by fostering M2 macrophage polarization. In gastric cancer, the TLR2/MyD88 axis drives tumor cell stemness within the inflammatory microenvironment created by Helicobacter pylori infection, with TLR2 simultaneously inducing cytokines such as TNF-α and GM-CSF while suppressing the chemokines CXCL1 and CXCL8. In skin carcinogenesis, MyD88-dependent NF-κB activation is required for the pro-inflammatory response of oncogenic RAS in keratinocytes, and TLR4, activated by high mobility group box-1 protein, accelerates melanoma progression. In pancreatic cancer, TLR7/MyD88 signaling activates STAT3, NF-κB, and MAPK to promote tumor initiation, and MyD88 blockade dramatically ameliorated cachexia-associated anorexia, fatigue, and muscle wasting in models of pancreatic ductal adenocarcinoma.
Yet the review’s most provocative theme is that MyD88 is a double-edged sword. In some settings, its absence worsens disease. In DSS-induced colitis, MyD88 in macrophages maintains intestinal homeostasis; its deficiency upregulates S100A8, activating the NLRP3 inflammasome and pyroptosis in epithelial cells via a RAGE-dependent pathway. MyD88 knockout mice are more susceptible to AOM/DSS-induced colitis-associated cancer, partly because IL-18 receptor signaling, which regulates dendritic cells and IL-22-binding protein secretion by Th17 and Th22 cells, depends on MyD88 to drive epithelial repair. In the authors’ own experiments, systemic MyD88 inhibition accelerated the growth of established H22 liver tumors, and H22 cells implanted in MyD88 knockout mice grew faster than in wild-type animals, indicating that MyD88-mediated anti-tumor inflammation is essential once cancer has taken hold. Similar protective roles for TLR4 have been reported in DMBA-induced skin and breast cancer models.
The authors conclude that timing, location, duration, dosage, and formulation of any MyD88 intervention may determine whether the outcome is protective or harmful, since inhibiting the adaptor can simultaneously weaken immune surveillance against tumor cells and relieve inflammation-driven tumorigenesis. Drug development faces further hurdles: many candidate MyD88 inhibitors suffer from low bioavailability, short half-lives, and poor pharmacokinetics, and clinical trials remain scarce, with most evidence drawn from animal studies. Encouragingly, the inhibitor TJ-M2010-6 produced no significant weight loss or increased infection rates in mice. As the first example of a malignancy driven by a single dominant mutation, Waldenström’s macroglobulinemia demonstrates how targeting the MyD88 axis, directly or through partners such as BTK, can yield striking clinical benefit. The review argues that integrating MyD88-targeted therapy with immunotherapeutic approaches could reshape cancer treatment, provided researchers can resolve the biphasic biology of this indispensable, and occasionally dangerous, immune adaptor.
Subject of Research: The role of the MyD88 adaptor protein in tumor initiation and progression
Article Title: MyD88’s function in the emergence and growth of tumors
Article References: Liu, J., Zhu, S., Huang, Q., Yao, Y., Li, W., & Zhang, S. (2024). MyD88’s function in the emergence and growth of tumors. Clinical Cancer Bulletin, 3(1), Article 19. https://doi.org/10.1007/s44272-024-00023-x
Image Credits: AI Generated
DOI: 10.1007/s44272-024-00023-x
Keywords: MyD88, Toll-like receptors, NF-κB, Waldenström’s macroglobulinemia, MYD88 L265P, colorectal cancer, hepatocellular carcinoma, inflammation, tumor microenvironment, BTK inhibitor, IRAK4, cancer immunotherapy
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Nathaniel Bowman. (October 4, 2026). The Immune Adaptor MyD88 Emerges as a Double-Edged Sword in Cancer. Scienmag. https://scienmag.com/the-immune-adaptor-myd88-emerges-as-a-double-edged-sword-in-cancer/
Nathaniel Bowman. “The Immune Adaptor MyD88 Emerges as a Double-Edged Sword in Cancer.” Scienmag, 4 October 2026, https://scienmag.com/the-immune-adaptor-myd88-emerges-as-a-double-edged-sword-in-cancer/. Accessed 4 October 2026.
Nathaniel Bowman. “The Immune Adaptor MyD88 Emerges as a Double-Edged Sword in Cancer.” Scienmag. October 4, 2026. https://scienmag.com/the-immune-adaptor-myd88-emerges-as-a-double-edged-sword-in-cancer/
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Tags: BTK inhibitorcancer immunotherapyColorectal cancerhepatocellular carcinomaimmune adaptor proteins in cancer biologyimmune signaling pathways in tumor microenvironmentinflammationinnate immunity and tumor progressionIRAK4molecular mechanisms of TLR-mediated cancer growthMyD88MyD88 as a double-edged sword in oncologyMYD88 L265PMyD88 signaling pathwaymyeloid differentiation and immune responseNF-κBNF-κB activation in cancerrole of MyD88 in blood and solid tumorstherapeutic targeting of MyD88 in cancerTLRs and pattern recognition receptorsToll-like receptor signaling in cancerToll-like receptorstumor microenvironmentWaldenström’s macroglobulinemia
