BTK inhibitors touch myeloid Fc receptor biology sideways, and the macrophage/dendritic-cell evidence is mostly distal

Question: How do BTK inhibitors such as ibrutinib and acalabrutinib modulate Fc receptor signaling in myeloid cells beyond neutrophils, including macrophages and dendritic cells?

Answer

Taken together, the retrieved papers support a narrower and more cautious answer than the question presumes: BTK is formally part of the Fc receptor signalosome and is expressed in macrophages, microglia, and dendritic cells, but no retrieved study actually measures FcγR-proximal signaling in macrophages or dendritic cells under ibrutinib or acalabrutinib. What the corpus supports is that BTK blockade changes myeloid outcomes associated with FcR-dependent function — clearance of opsonized or particulate cargo, invasive behaviour, inflammatory polarization, tertiary lymphoid structure formation — while the receptor-proximal mechanism is inferred rather than demonstrated. Two further constraints emerge across these papers: BTK's contribution to myeloid biology is heavily scaffold- as well as kinase-dependent, which is exactly the fraction covalent inhibitors such as ibrutinib and acalabrutinib do not address, and the strongest documented BTK substrate in human macrophages in this corpus is NLRP3 rather than any FcR component. The literature is therefore consistent with BTK inhibitors modulating FcR-driven myeloid behaviour indirectly and incompletely, and it does not support a mechanistic claim about drug-specific effects on FcγR signaling in these cells.

BTK is assigned to the Fc receptor signalosome largely by pathway annotation, not by perturbation

BTK is described as transducing B cell receptor, Toll-like receptor, and Fc receptor signaling, with the explicit framing that small-molecule inhibition of BTK's enzymatic function is undermined by resistance mutations that abolish kinase activity yet promote oncogenic signaling through BTK scaffolding functions [2]. The receptor-proximal FcγR cascade in macrophages is being resolved at the level of Syk, where phagocytosis induces DHHC5-dependent Syk palmitoylation required for Syk localization to the phagocytic cup, Cdc42 recruitment, F-actin polymerization and uptake, plus a second, redox-sensitive cysteine whose desulfenylation is required for catalytic activity [6]. Downstream of Syk, IgG-mediated phagocytosis proceeds through Syk phosphorylation of the GEF Vav1 and Rac-driven F-actin rearrangement, and this step is where the inhibitory receptor CD47/SIRPα acts, blocking Vav1 phosphorylation without affecting Syk phosphorylation or Vav1 recruitment [9]. None of these mechanistic maps places BTK in the measured cascade; BTK's inclusion is asserted at the level of pathway membership rather than tested at the level of a specific phosphorylation event in macrophages.

In macrophages and microglia, BTK blockade suppresses clearance and pro-invasive functions, but readouts sit downstream of the receptor

In glioblastoma, BTK is predominantly expressed in tumor-infiltrating myeloid cells, and BTK inhibition with ibrutinib suppresses clearance of oncolytic herpes simplex virus by tumor-infiltrating microglia and macrophages while reducing their pro-invasive effects on tumor cells [10]. In intracerebral hemorrhage, inhibiting BTK with ibrutinib alleviated neurological deficits and neuroinflammation in mice, microglia were the brain immune cells expressing the most BTK, and BTK_high microglia showed lower expression of anti-inflammatory and phagocytosis-related pathways than BTK_low microglia, with BTK_high cells tending toward M1 and M2b polarization states [11]. Both studies establish that ibrutinib engages BTK in macrophages or microglia and shifts clearance and activation phenotypes, but neither isolates an Fc receptor as the input, and the two point in opposite directions on phagocytosis — ibrutinib suppressing myeloid clearance in one system and high BTK marking lower phagocytic pathway expression in the other.

Dendritic cells are treated as part of a bulk myeloid BTK effect rather than as a separately resolved FcR compartment

BTK is reported to regulate the activity of tumor-infiltrating myeloid cells including dendritic cells, macrophages, and microglia in brain tumors, with high BTK expression associated with poor glioma survival, and ibrutinib combined with oncolytic virus modified key signaling pathways in tumor-infiltrating macrophages and microglia by single-cell RNA sequencing while promoting formation of tumor-infiltrating tertiary lymphoid structures [10]. That is the extent of the retrieved dendritic cell evidence: dendritic cells are named in the expressing compartment and included in bulk and single-cell analyses, but no retrieved paper reports an FcγR stimulation experiment, an immune-complex uptake assay, or a cross-presentation readout in dendritic cells treated with a BTK inhibitor.

The best-documented BTK-dependent event in human macrophages is inflammasome phosphorylation, not Fc receptor signaling

Human resistin binds BTK in human macrophages, causing BTK autophosphorylation and BTK-dependent phosphorylation of NLRP3, leading to inflammasome assembly and IL-1β/IL-18 secretion, with colocalization of resistin, BTK and NLRP3 in macrophages increased in pulmonary hypertension patient lungs [12]. This is a direct, human, macrophage-intrinsic BTK substrate and it is an inflammasome node, not an FcR node. It matters for the question because it supplies a plausible alternative explanation for inflammatory phenotypes attributed to FcR modulation: a BTK inhibitor given to macrophages will hit this axis regardless of whether any FcγR is engaged.

Attributing BTK-inhibitor effects to Fc receptor blockade is confounded by how FcR engagement itself reprograms macrophages

Antibody-dependent phagocytosis of cancer cells drives macrophages into an anti-inflammatory, immunosuppressive gene regulatory program with pro-angiogenic chemokine expression and stress transcription factor activity, a program shared with apoptotic-cell phagocytosis in addition to substrate-specific pathways [7]. Macrophage state is also dissociable from uptake route: β-glucan-induced trained immunity reduced efferocytosis of apoptotic tumor cells without affecting antibody-opsonized ADCP [5]. And FcR engagement does not even reliably predict engulfment, since target cell adhesion limits phagocytosis and promotes trogocytosis [3] and target cortical tension switches macrophages between trogocytosis and phagocytosis [8]. Any measurement of "FcR function" under ibrutinib or acalabrutinib therefore reports a composite of receptor signaling, downstream transcriptional reprogramming, and target mechanics.

Conflicts and gaps

The retrieved corpus contains no dose-response study of ibrutinib or acalabrutinib on FcγR-stimulated macrophages or dendritic cells, and acalabrutinib does not appear in any retrieved abstract — so no comparison between the two drugs, and none against zanubrutinib or the BTK degrader, is possible from this evidence base. The directional conflict between ibrutinib suppressing myeloid clearance of oncolytic virus [10] and high BTK expression marking reduced phagocytosis-related pathway expression in microglia [11] is unresolved. The scaffold-versus-kinase problem is acknowledged for BTK generally [2] but never tested for an FcR output, leaving open whether the FcR-relevant fraction of BTK function is inhibitor-refractory. The FcR field's own mechanistic work proceeds without BTK: the inhibitory receptor FcγRIIB sets the duration of IgG signaling by converting PI(3,4,5)P3 to PI(3,4)P2 so that activating receptors control sensitivity while FcγRIIB controls duration [1], and IgG engagement enhances phagosome maturation through p38α MAPK [4]; neither study measures BTK, so where BTK sits relative to the duration-versus-sensitivity division of labour is unestablished.

What would change the answer

A phosphoproteomic time course of FcγR crosslinking in human monocyte-derived macrophages and in cDC1/cDC2 subsets, treated with ibrutinib, acalabrutinib, zanubrutinib, and pirtobrutinib at clinically achievable free concentrations, quantifying BTK pY223/pS180, PLCγ2, Syk, and Akt, would establish whether the receptor-proximal axis is touched at all. Parallel arms with a BTK degrader such as bexobrutideg [2] and with a kinase-dead or C481S BTK knock-in would separate kinase from scaffold contributions. Functional readouts should use the controllable chimeric FcR system that independently tunes activating and inhibitory receptor engagement [1], paired with donor-matched ADCP and trogocytosis assays on targets of defined adhesion and tension [3] [8]. In vivo, myeloid-conditional Btk deletion compared against pharmacological BTK inhibition in the glioblastoma and intracerebral hemorrhage models [10] [11] would show whether the clearance phenotypes are on-target for BTK and FcR-dependent.

References

[1] Bond, A., Snyder, E. T., Manion, A., Hardy, C., Kieu, K., Wilson, M. Z., Yeung, E. A., Morrissey, M. A.. "Inhibitory Fc Receptor sets a time limit on macrophage response to IgG". bioRxiv. 2026-10-02T00:00:00.000Z. URL: https://doi.org/10.64898/2026.09.21.753242

[2] Noviski, M., Auger, P., Bautista, D., Brathaban, N., Bravo, B., Cass, R., Cherala, G., Fung, T. C., Gajewski, S., Haria, D., Jiang, Z., Karr, D., Kelly, A., Kato, D., Konst, Z. A., Kumar, A., Lavarias, M., Ma, J., Marchioni, F., McIntosh, J., McKinnell, J., Mihalic, J. T., Mukerji, R., Murphy, B., Narasappa, N., Peng, G., Reddy, P. J., Robbins, D. W., Rountree, R., Singh, S., Tan, Y. S., Tenn-McClellan, A., Weiss, D. R., Wu, J., Ye, J., Yung, S., Messmer, D., Guiducci, C., Sands, A. T., Hansen, G. M., Cohen, F.. "Bexobrutideg: A Selective, Catalytic Degrader of Bruton's Tyrosine Kinase Overcomes Inhibitor Resistance and Suppresses Autoantibody-Mediated Disease". bioRxiv. 2026-08-04T00:00:00.000Z. URL: https://doi.org/10.64898/2026.08.01.740538

[3] Rollins, K. R., Fiaz, S., Morrissey, M. A.. "Target cell adhesion limits macrophage phagocytosis and promotes trogocytosis". bioRxiv. 2025-02-08T00:00:00.000Z. URL: https://doi.org/10.1101/2025.02.06.636906

[4] Shah, M., Kirthivasan, N., Chakraborty, S., Krishnan, Y., Jhunjhunwala, S.. "Phagosome Maturation in Macrophages is Enhanced by p38α MAPK Signaling". bioRxiv. 2025-07-06T00:00:00.000Z. URL: https://doi.org/10.1101/2025.07.03.662985

[5] Chatzis, A., Lukaszonek, J., Lagos, D., Boucher, D., Kourtzelis, I.. "β-glucan reprograms macrophages to attenuate efferocytosis of cancer cells". bioRxiv. 2025-07-03T00:00:00.000Z. URL: https://doi.org/10.1101/2024.11.11.622862

[6] Jansen, M., Strub, J.-M., Chaloin, L., Coopman, P., Beaumelle, B.. "Syk activation during FcγR-mediated phagocytosis involves Syk palmitoylation and desulfenylation". bioRxiv. 2025-05-27T00:00:00.000Z. URL: https://doi.org/10.1101/2025.05.26.656092

[7] Zhang, C. R., Xiong, L., Gu, M., Yeh, C. Y., Jerby, L., Kundaje, A., Greenleaf, W. J., Bassik, M. C.. "Cancer cell phagocytosis induces an anti-inflammatory gene regulatory program in macrophages". bioRxiv. 2025-08-22T00:00:00.000Z. URL: https://doi.org/10.1101/2025.08.18.670953

[8] Cornell, C. E., Chorlay, A., Krishnamurthy, D., Martin, N. R., Baldauf, L., Fletcher, D. A.. "Target cell tension regulates macrophage trogocytosis". bioRxiv. 2024-12-05T00:00:00.000Z. URL: https://doi.org/10.1101/2024.12.02.626490

[9] Miller, W. D., Mishra, A. K., Sheedy, C. J., Bond, A., Gardner, B. M., Montell, D. J., Morrissey, M. A.. "CD47 prevents Rac-mediated phagocytosis through Vav1 dephosphorylation". bioRxiv. 2025-02-12T00:00:00.000Z. URL: https://doi.org/10.1101/2025.02.11.637707

[10] Kyritsi, K., Zhu, D., Ding, H., Friedman, G. K., Lv, D., Wang, M., Mivechi, N. F., Kollhe, R., Johnson, T. S., Kaur, B., Munn, D. H., Hong, B.. "BTK inhibition enhances immunovirotherapy in glioblastoma via tertiary lymphoid structure modulation". bioRxiv. 2026-06-04T00:00:00.000Z. URL: https://doi.org/10.64898/2026.06.01.729275

[11] Xia, S., Chen, G.. "BTK promotes neuroinflammation by interacting with hub genes and modulating microglia following intracerebral hemorrhage". bioRxiv. 2026-03-06T00:00:00.000Z. URL: https://doi.org/10.64898/2026.03.04.709243

[12] Kariyawasam, U., Skinner, J., Lam, W., Chakrabarti, R., Cox, A., Hassoun, P. M., Lin, Q., Johns, R.. "Human resistin is critical to activation of the NLRP3 inflammasome in macrophages". bioRxiv. 2025-11-14T00:00:00.000Z. URL: https://doi.org/10.1101/2025.11.13.688330