Antibody-lectin chimeras for glyco-immune checkpoint blockade

Prasad, V., Haslam, A. & Olivier, T. Updated estimates of eligibility and response: immune checkpoint inhibitors. J. Clin. Oncol. 42, e14613 (2024).
Google Scholar
Schachter, J. et al. Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet 390, 1853–1862 (2017).
Google Scholar
RodrÍguez, E., Schetters, S. T. T. & van Kooyk, Y. The tumour glyco-code as a novel immune checkpoint for immunotherapy. Nat. Rev. Immunol. 18, 204–211 (2018).
Google Scholar
Rodrigues Mantuano, N., Natoli, M., Zippelius, A. & Läubli, H. Tumor-associated carbohydrates and immunomodulatory lectins as targets for cancer immunotherapy. J. Immunother. Cancer 8, e001222 (2020).
Google Scholar
Läubli, H. & Borsig, L. Altered cell adhesion and glycosylation promote cancer immune suppression and metastasis. Front. Immunol. 10, 2120 (2019).
Google Scholar
Smith, B. A. H. & Bertozzi, C. R. The clinical impact of glycobiology: targeting selectins, Siglecs and mammalian glycans. Nat. Rev. Drug Discov. 20, 217–243 (2021).
Google Scholar
Natoni, A., Macauley, M. S. & O’Dwyer, M. E. Targeting selectins and their ligands in cancer. Front. Oncol. 6, 93 (2016).
Google Scholar
Liu, F.-T. & Rabinovich, G. A. Galectins as modulators of tumour progression. Nat. Rev. Cancer 5, 29–41 (2005).
Google Scholar
Mariño, K. V., Cagnoni, A. J., Croci, D. O. & Rabinovich, G. A. Targeting galectin-driven regulatory circuits in cancer and fibrosis. Nat. Rev. Drug Discov. 22, 295–316 (2023).
Google Scholar
Bandala-Sanchez, E. et al. T cell regulation mediated by interaction of soluble CD52 with the inhibitory receptor Siglec-10. Nat. Immunol. 14, 741–748 (2013).
Google Scholar
Laubli, H. et al. Engagement of myelomonocytic Siglecs by tumor-associated ligands modulates the innate immune response to cancer. Proc. Natl Acad. Sci. USA 111, 14211–14216 (2014).
Google Scholar
Xiao, H., Woods, E. C., Vukojicic, P. & Bertozzi, C. R. Precision glycocalyx editing as a strategy for cancer immunotherapy. Proc. Natl Acad. Sci. USA 113, 10304–10309 (2016).
Google Scholar
Stanczak, M. A. et al. Self-associated molecular patterns mediate cancer immune evasion by engaging Siglecs on T cells. J. Clin. Invest. 128, 4912–4923 (2018).
Google Scholar
Wang, J. et al. Siglec-15 as an immune suppressor and potential target for normalization cancer immunotherapy. Nat. Med. 25, 656–666 (2019).
Google Scholar
Barkal, A. A. et al. CD24 signalling through macrophage Siglec-10 is a target for cancer immunotherapy. Nature 572, 392–396 (2019).
Google Scholar
Gray, M. A. et al. Targeted glycan degradation potentiates the anticancer immune response in vivo. Nat. Chem. Biol. 16, 1376–1384 (2020).
Google Scholar
Wisnovsky, S. et al. Genome-wide CRISPR screens reveal a specific ligand for the glycan-binding immune checkpoint receptor Siglec-7. Proc. Natl Acad. Sci. USA 118, e2015024118 (2021).
Google Scholar
Rodriguez, E. et al. Sialic acids in pancreatic cancer cells drive tumour-associated macrophage differentiation via the Siglec receptors Siglec-7 and Siglec-9. Nat. Commun. 12, 1270 (2021).
Google Scholar
Haas, Q. et al. Siglec-9 regulates an effector memory CD8+ T-cell subset that congregates in the melanoma tumor microenvironment. Cancer Immunol. Res. 7, 707–718 (2019).
Google Scholar
Ibarlucea-Benitez, I., Weitzenfeld, P., Smith, P. & Ravetch, J. V. Siglecs-7/9 function as inhibitory immune checkpoints in vivo and can be targeted to enhance therapeutic antitumor immunity. Proc. Natl Acad. Sci. USA 118, e2107424118 (2021).
Google Scholar
Haas, Q. et al. Siglec-7 represents a glyco-immune checkpoint for non-exhausted effector memory CD8+ T cells with high functional and metabolic capacities. Front. Immunol. 13, 996746 (2022).
Google Scholar
Stanczak, M. A. et al. Targeting cancer glycosylation repolarizes tumor-associated macrophages allowing effective immune checkpoint blockade. Sci. Transl. Med. 14, eabj1270 (2022).
Google Scholar
Theruvath, J. et al. Anti-GD2 synergizes with CD47 blockade to mediate tumor eradication. Nat. Med. 28, 333–344 (2022).
Google Scholar
Daly, J. et al. Targeting hypersialylation in multiple myeloma represents a novel approach to enhance NK cell-mediated tumor responses. Blood Adv. 6, 3352–3366 (2022).
Google Scholar
Schmassmann, P. et al. Targeting the Siglec–sialic acid axis promotes antitumor immune responses in preclinical models of glioblastoma. Sci. Transl. Med. 15, eadf5302 (2023).
Google Scholar
Bordoloi, D. et al. Siglec-7 glyco-immune binding mAbs or NK cell engager biologics induce potent antitumor immunity against ovarian cancers. Sci. Adv. 9, eadh4379 (2023).
Google Scholar
Szijj, P. A. et al. Chemical generation of checkpoint inhibitory T cell engagers for the treatment of cancer. Nat. Chem. 15, 1636–1647 (2023).
Google Scholar
Egan, H. et al. Targeting stromal cell sialylation reverses T cell-mediated immunosuppression in the tumor microenvironment. Cell Rep. 42, 112475 (2023).
Google Scholar
Lustig, M. et al. Disruption of the sialic acid/Siglec-9 axis improves antibody-mediated neutrophil cytotoxicity towards tumor cells. Front. Immunol. 14, 1178817 (2023).
Google Scholar
Mei, Y. et al. Siglec-9 acts as an immune-checkpoint molecule on macrophages in glioblastoma, restricting T-cell priming and immunotherapy response. Nat. Cancer 4, 1273–1291 (2023).
Google Scholar
Yang, Z. et al. Targeted desialylation and cytolysis of tumour cells by fusing a sialidase to a bispecific T-cell engager. Nat. Biomed. Eng. 8, 499–512 (2024).
Google Scholar
Wang, Y. et al. Siglec-15/sialic acid axis as a central glyco-immune checkpoint in breast cancer bone metastasis. Proc. Natl Acad. Sci. USA 121, e2312929121 (2024).
Google Scholar
Wen, R. M. et al. Sialylated glycoproteins suppress immune cell killing by binding to Siglec-7 and Siglec-9 in prostate cancer. J. Clin. Invest. 134, e180282 (2024).
Google Scholar
O’Neill, A. et al. Stromal cells modulate innate immune cell phenotype and function in colorectal cancer via the sialic acid/Siglec axis. J. Immunother. Cancer 13, e012491 (2025).
Google Scholar
Sterner, E., Flanagan, N. & Gildersleeve, J. C. Perspectives on anti-glycan antibodies gleaned from development of a community resource database. ACS Chem. Biol. 11, 1773–1783 (2016).
Google Scholar
Smith, B. A. H. et al. MYC-driven synthesis of Siglec ligands is a glycoimmune checkpoint. Proc. Natl Acad. Sci. USA 120, e2215376120 (2023).
Google Scholar
Büll, C., Heise, T., Adema, G. J. & Boltje, T. J. Sialic acid mimetics to target the sialic acid–Siglec axis. Trends Biochem. Sci. 41, 519–531 (2016).
Google Scholar
Pedram, K. et al. Design of a mucin-selective protease for targeted degradation of cancer-associated mucins. Nat. Biotechnol. 42, 597–607 (2024).
Google Scholar
Filipovic, A. et al. Phase1/2 study of an anti-galectin-9 antibody, LYT-200, in patients with metastatic solid tumors. J. Immunother. Cancer 9, A512 (2021).
Shum, E., et al. Clinical benefit through Siglec-15 targeting with NC318 antibody in subjects with Siglec-15 positive advanced solid tumors. J. Immunother. Cancer 9, A520–A521 (2021).
Luke, J. J. et al. Abstract CT034: GLIMMER-01: initial results from a phase 1 dose escalation trial of a first-in-class bi-sialidase (E-602) in solid tumors. Cancer Res. 83, CT034 (2023).
Google Scholar
Dimitriou, F. et al. Frequency, treatment and outcome of immune-related toxicities in patients with immune-checkpoint inhibitors for advanced melanoma: results from an institutional database analysis. Cancers 13, 2931 (2021).
Google Scholar
NextCure, Inc. A safety and tolerability study of NC318 in subjects with advanced or metastatic solid tumors. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT03665285 (2025).
Perez, E. A. et al. Incidence of adverse events with therapies targeting HER2-positive metastatic breast cancer: a literature review. Breast Cancer Res. Treat. 194, 1–11 (2022).
Google Scholar
Sakuishi, K. et al. Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J. Exp. Med. 207, 2187–2194 (2010).
Google Scholar
Yang, R. et al. Galectin-9 interacts with PD-1 and TIM-3 to regulate T cell death and is a target for cancer immunotherapy. Nat. Commun. 12, 832 (2021).
Google Scholar
Park, S. et al. The therapeutic effect of anti-HER2/neu antibody depends on both innate and adaptive immunity. Cancer Cell 18, 160–170 (2010).
Google Scholar
Gullo, G., Zuradelli, M., Sclafani, F., Santoro, A. & Crown, J. Durable complete response following chemotherapy and trastuzumab for metastatic HER2-positive breast cancer. Ann. Oncol. 23, 2204–2205 (2012).
Google Scholar
Witzel, I. et al. Long-term tumor remission under trastuzumab treatment for HER2 positive metastatic breast cancer—results from the HER-OS patient registry. BMC Cancer 14, 806 (2014).
Google Scholar
Slamon, D. J. et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N. Engl. J. Med. 344, 783–792 (2001).
Google Scholar
Bang, Y.-J. et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 376, 687–697 (2010).
Google Scholar
Rugo, H. S. et al. Efficacy of margetuximab vs trastuzumab in patients with pretreated ERBB2-positive advanced breast cancer: a phase 3 randomized clinical trial. JAMA Oncol. 7, 573–584 (2021).
Google Scholar
Merchant, A. M. et al. An efficient route to human bispecific IgG. Nat. Biotechnol. 16, 677–681 (1998).
Google Scholar
Delaveris, C. S., Chiu, S. H., Riley, N. M. & Bertozzi, C. R. Modulation of immune cell reactivity with cis-binding Siglec agonists. Proc. Natl Acad. Sci. USA 118, e2012408118 (2021).
Google Scholar
Bruncsics, B., Errington, W. J. & Sarkar, C. A. MVsim is a toolset for quantifying and designing multivalent interactions. Nat. Commun. 13, 117 (2022).
Google Scholar
Errington, W. J., Bruncsics, B. & Sarkar, C. A. Mechanisms of noncanonical binding dynamics in multivalent protein–protein interactions. Proc. Natl Acad. Sci. USA 116, 25659–25667 (2019).
Google Scholar
Gasparrini, F. et al. Nanoscale organization and dynamics of the siglec CD22 cooperate with the cytoskeleton in restraining BCR signalling. EMBO J. 35, 258–280 (2016).
Google Scholar
Spence, S. et al. Targeting Siglecs with a sialic acid-decorated nanoparticle abrogates inflammation. Sci. Transl. Med. 7, 303ra140 (2015).
Google Scholar
McCord, K. A. et al. Dissecting the ability of Siglecs to antagonize Fcγ receptors. ACS Cent. Sci. 10, 315–330 (2024).
Google Scholar
Mazor, Y. et al. Improving target cell specificity using a novel monovalent bispecific IgG design. MAbs 7, 377–389 (2015).
Google Scholar
Elliott, J. M. et al. Antiparallel conformation of knob and hole aglycosylated half-antibody homodimers is mediated by a CH2–CH3 hydrophobic interaction. J. Mol. Biol. 426, 1947–1957 (2014).
Google Scholar
Angata, T., von Gunten, S., Schnaar, R. L. & Varki, A. I-type lectins. In Essentials of Glycobiology (eds Varki, A. et al.) 475–490 (Cold Spring Harbor Laboratory Press, 2022).
Smith, P., DiLillo, D. J., Bournazos, S., Li, F. & Ravetch, J. V. Mouse model recapitulating human Fcγ receptor structural and functional diversity. Proc. Natl Acad. Sci. USA 109, 6181–6186 (2012).
Google Scholar
Sharma, P. & Allison, J. P. Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell 161, 205–214 (2015).
Google Scholar
Morrissey, M. A., Kern, N. & Vale, R. D. CD47 ligation repositions the inhibitory receptor SIRPA to suppress integrin activation and phagocytosis. Immunity 53, 290–302.e6 (2020).
Google Scholar
Miller, W. D. et al. CD47 inhibits phagocytosis through Vav dephosphorylation. J. Cell Biol. 224, e202502206 (2025).
Google Scholar
Upton, R. et al. Combining CD47 blockade with trastuzumab eliminates HER2-positive breast cancer cells and overcomes trastuzumab tolerance. Proc. Natl Acad. Sci. USA 118, e2026849118 (2021).
Google Scholar
Shitara, K. et al. Final analysis of the randomized phase 2 part of the ASPEN-06 study: a phase 2/3 study of evorpacept (ALX148), a CD47 myeloid checkpoint inhibitor, in patients with HER2-overexpressing gastric/gastroesophageal cancer (GC). J. Clin. Oncol. 43, 332 (2025).
Google Scholar
Daver, N. et al. The ENHANCE-3 study: venetoclax and azacitidine plus magrolimab or placebo for untreated AML unfit for intensive therapy. Blood 146, 601–611 (2025).
Google Scholar
Wilcke, M. et al. Rab11 regulates the compartmentalization of early endosomes required for efficient transport from early endosomes to the trans-Golgi network. J. Cell Biol. 151, 1207–1220 (2000).
Google Scholar
Fairn, G. D. & Grinstein, S. How nascent phagosomes mature to become phagolysosomes. Trends Immunol. 33, 397–405 (2012).
Google Scholar
Jiang, C. et al. Inactivation of Rab11a GTPase in macrophages facilitates phagocytosis of apoptotic neutrophils. J. Immunol. 198, 1660–1672 (2017).
Google Scholar
Krug, K. et al. A curated resource for phosphosite-specific signature analysis. Mol. Cell. Proteom. 18, 576–593 (2019).
Google Scholar
Scatizzi, J. C. et al. The CDK domain of p21 is a suppressor of IL-1β-mediated inflammation in activated macrophages: innate immunity. Eur. J. Immunol. 39, 820–825 (2009).
Google Scholar
Lloberas, J. & Celada, A. p21(waf1/CIP1), a CDK inhibitor and a negative feedback system that controls macrophage activation: HIGHLIGHTS. Eur. J. Immunol. 39, 691–694 (2009).
Google Scholar
Xu, J. et al. Inhibition of cyclin-dependent kinase 2 signaling prevents liver ischemia and reperfusion injury. Transplantation 103, 724–732 (2019).
Google Scholar
Nunes, M. P. et al. Inhibitory effects of Trypanosoma cruzi sialoglycoproteins on CD4+ T cells are associated with increased susceptibility to infection. PLoS ONE 8, e77568 (2013).
Google Scholar
Tarantino, P. et al. HER2-low breast cancer: pathological and clinical landscape. J. Clin. Orthod. 38, 1951–1962 (2020).
Google Scholar
Mittendorf, E. A. et al. Loss of HER2 amplification following trastuzumab-based neoadjuvant systemic therapy and survival outcomes. Clin. Cancer Res. 15, 7381–7388 (2009).
Google Scholar
Jamal-Hanjani, M. et al. Tracking the evolution of non-small-cell lung cancer. N. Engl. J. Med. 376, 2109–2121 (2017).
Google Scholar
Walker, A. J. et al. Tumor antigen and receptor densities regulate efficacy of a chimeric antigen receptor targeting anaplastic lymphoma kinase. Mol. Ther. 25, 2189–2201 (2017).
Google Scholar
Majzner, R. G. & Mackall, C. L. Tumor antigen escape from CAR T-cell therapy. Cancer Discov. 8, 1219–1226 (2018).
Google Scholar
Advani, R. et al. CD47 blockade by Hu5F9-G4 and rituximab in non-Hodgkin’s lymphoma. N. Engl. J. Med. 379, 1711–1721 (2018).
Google Scholar
Chao, M. P. et al. Anti-CD47 antibody synergizes with rituximab to promote phagocytosis and eradicate non-Hodgkin lymphoma. Cell 142, 699–713 (2010).
Google Scholar
Wolchok, J. D. et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N. Engl. J. Med. 377, 1345–1356 (2017).
Google Scholar
Rosenberg, S. A. et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin. Cancer Res. 17, 4550–4557 (2011).
Google Scholar
Porter, D. L., Levine, B. L., Kalos, M., Bagg, A. & June, C. H. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N. Engl. J. Med. 365, 725–733 (2011).
Google Scholar
Espinosa-Carrasco, G. et al. Intratumoral immune triads are required for immunotherapy-mediated elimination of solid tumors. Cancer Cell 42, 1202–1216.e8 (2024).
Google Scholar
Magen, A. et al. Intratumoral dendritic cell–CD4+ T helper cell niches enable CD8+ T cell differentiation following PD-1 blockade in hepatocellular carcinoma. Nat. Med. 29, 1389–1399 (2023).
Google Scholar
Sharma, P., Hu-Lieskovan, S., Wargo, J. A. & Ribas, A. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell 168, 707–723 (2017).
Google Scholar
Fraietta, J. A. et al. Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia. Nat. Med. 24, 563–571 (2018).
Google Scholar
Zhu, C. et al. The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nat. Immunol. 6, 1245–1252 (2005).
Google Scholar
Stillman, B. N. et al. Galectin-3 and galectin-1 bind distinct cell surface glycoprotein receptors to induce T cell death. J. Immunol. 176, 778–789 (2006).
Google Scholar
Toscano, M. A. et al. Differential glycosylation of TH1, TH2 and TH-17 effector cells selectively regulates susceptibility to cell death. Nat. Immunol. 8, 825–834 (2007).
Google Scholar
Jin, H.-T. et al. Cooperation of Tim-3 and PD-1 in CD8 T-cell exhaustion during chronic viral infection. Proc. Natl Acad. Sci. USA 107, 14733–14738 (2010).
Google Scholar
Cagnoni, A. J. et al. Galectin-1 fosters an immunosuppressive microenvironment in colorectal cancer by reprogramming CD8+ regulatory T cells. Proc. Natl Acad. Sci. USA 118, e2102950118 (2021).
Google Scholar
Hodi, F. S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010).
Google Scholar
Overman, M. J. et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J. Clin. Oncol. 36, 773–779 (2018).
Google Scholar
Le, D. T. et al. Phase II open-label study of pembrolizumab in treatment-refractory, microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: KEYNOTE-164. J. Clin. Oncol. 38, 11–19 (2020).
Google Scholar
Motzer, R. J. et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N. Engl. J. Med. 378, 1277–1290 (2018).
Google Scholar
Choueiri, T. K. et al. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N. Engl. J. Med. 384, 829–841 (2021).
Google Scholar
Rini, B. I. et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N. Engl. J. Med. 380, 1116–1127 (2019).
Google Scholar
Reck, M. et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N. Engl. J. Med. 375, 1823–1833 (2016).
Google Scholar
Cascone, T. et al. Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial. Nat. Med. 27, 504–514 (2021).
Google Scholar
Borate, U., et al. Phase Ib study of the anti-TIM-3 antibody MBG453 in combination with decitabine in patients with high-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Blood 134, 570 (2019).
Google Scholar
Acharya, N., Sabatos-Peyton, C. & Anderson, A. C. Tim-3 finds its place in the cancer immunotherapy landscape. J. Immunother. Cancer 8, e000911 (2020).
Google Scholar
Curigliano, G. et al. Phase I/Ib clinical trial of sabatolimab, an anti-TIM-3 antibody, alone and in combination with spartalizumab, an anti-PD-1 antibody, in advanced solid tumors. Clin. Cancer Res. 27, 3620–3629 (2021).
Google Scholar
Kaufman, H. L. et al. Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial. Lancet Oncol. 17, 1374–1385 (2016).
Google Scholar
Motzer, R. J. et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N. Engl. J. Med. 380, 1103–1115 (2019).
Google Scholar
Powles, T. et al. Avelumab maintenance therapy for advanced or metastatic urothelial carcinoma. N. Engl. J. Med. 383, 1218–1230 (2020).
Google Scholar
Garnham, R. et al. ST3 beta-galactoside alpha-23-sialyltransferase 1 (ST3Gal1) synthesis of Siglec ligands mediates anti-tumour immunity in prostate cancer. Commun. Biol. 7, 276 (2024).
Google Scholar
Duxfield, A. et al. The androgen receptor and MYC synergise to modulate the synthesis of Siglec-7 ligands in prostate cancer. Preprint at bioRxiv https://doi.org/10.1101/2025.10.15.682547 (2025).
Daley, D. et al. Dectin 1 activation on macrophages by galectin 9 promotes pancreatic carcinoma and peritumoral immune tolerance. Nat. Med. 23, 556–567 (2017).
Google Scholar
Fernandes, R. A. et al. Immune receptor inhibition through enforced phosphatase recruitment. Nature 586, 779–784 (2020).
Google Scholar
Lippert, A. H. et al. Antibody agonists trigger immune receptor signaling through local exclusion of receptor-type protein tyrosine phosphatases. Immunity 57, 256–270.e10 (2024).
Google Scholar
Juszczynski, P. et al. The AP1-dependent secretion of galectin-1 by Reed Sternberg cells fosters immune privilege in classical Hodgkin lymphoma. Proc. Natl Acad. Sci. USA 104, 13134–13139 (2007).
Google Scholar
Ilarregui, J. M. et al. Tolerogenic signals delivered by dendritic cells to T cells through a galectin-1-driven immunoregulatory circuit involving interleukin 27 and interleukin 10. Nat. Immunol. 10, 981–991 (2009).
Google Scholar
Dardalhon, V. et al. Tim-3/galectin-9 pathway: regulation of Th1 immunity through promotion of CD11b+Ly−6G+ myeloid cells. J. Immunol. 185, 1383–1392 (2010).
Google Scholar
Zhou, Q. et al. Coexpression of Tim-3 and PD-1 identifies a CD8+ T-cell exhaustion phenotype in mice with disseminated acute myelogenous leukemia. Blood 117, 4501–4510 (2011).
Google Scholar
Kouo, T. et al. Galectin-3 shapes antitumor immune responses by suppressing CD8+ T cells via LAG-3 and inhibiting expansion of plasmacytoid dendritic cells. Cancer Immunol. Res 3, 412–423 (2015).
Google Scholar
Tiraboschi, C. et al. Combining inhibition of galectin-3 with and before a therapeutic vaccination is critical for the prostate-tumor-free outcome. J. Immunother. Cancer 8, e001535 (2020).
Google Scholar
Sturgill, E. R. et al. Galectin-3 inhibition with belapectin combined with anti-OX40 therapy reprograms the tumor microenvironment to favor anti-tumor immunity. Oncoimmunology 10, 1892265 (2021).
Google Scholar
Li, Y. M. et al. Upregulation of CXCR4 is essential for HER2-mediated tumor metastasis. Cancer Cell 6, 459–469 (2004).
Google Scholar
Veth, T. S. et al. Improvements in glycoproteomics through architecture changes to the Orbitrap Tribrid MS platform. Anal. Chem. 97, 11413–11423 (2025).
Google Scholar
Elias, J. E. & Gygi, S. P. Target-decoy search strategy for increased confidence in large-scale protein identifications by mass spectrometry. Nat. Methods 4, 207–214 (2007).
Google Scholar
Yamaji, T., Teranishi, T., Alphey, M. S., Crocker, P. R. & Hashimoto, Y. A small region of the natural killer cell receptor, Siglec-7, is responsible for its preferred binding to alpha 2,8-disialyl and branched alpha 2,6-sialyl residues. A comparison with Siglec-9. J. Biol. Chem. 277, 6324–6332 (2002).
Google Scholar
Attrill, H. et al. Siglec-7 undergoes a major conformational change when complexed with the α(2,8)-disialylganglioside GT1b. J. Biol. Chem. 281, 32774–32783 (2006).
Google Scholar
Gasteiger, E. et al. ExPASy: the proteomics server for in-depth protein knowledge and analysis. Nucleic Acids Res. 31, 3784–3788 (2003).
Google Scholar
Wang, Y. et al. Specificity of mouse and human Fcgamma receptors and their polymorphic variants for IgG subclasses of different species. Eur. J. Immunol. 52, 753–759 (2022).
Google Scholar
Derer, S. et al. Increasing FcγRIIa affinity of an FcγRIII-optimized anti-EGFR antibody restores neutrophil-mediated cytotoxicity. MAbs 6, 409–421 (2014).
Google Scholar
Lohse, S. et al. An anti-EGFR IgA that displays improved pharmacokinetics and myeloid effector cell engagement in vivo. Cancer Res. 76, 403–417 (2016).
Google Scholar
HaileMariam, M. et al. S-Trap, an ultrafast sample-preparation approach for shotgun proteomics. J. Proteome Res. 17, 2917–2924 (2018).
Google Scholar
Zecha, J. et al. TMT labeling for the masses: a robust and cost-efficient, in-solution labeling approach. Mol. Cell. Proteom. 18, 1468–1478 (2019).
Google Scholar
Brenes, A., Hukelmann, J., Bensaddek, D. & Lamond, A. I. Multibatch TMT reveals false positives, batch effects and missing values. Mol. Cell. Proteom. 18, 1967–1980 (2019).
Google Scholar
Hebert, A. S. et al. Improved precursor characterization for data-dependent mass spectrometry. Anal. Chem. 90, 2333–2340 (2018).
Google Scholar
Zhou, H. et al. Robust phosphoproteome enrichment using monodisperse microsphere-based immobilized titanium (IV) ion affinity chromatography. Nat. Protoc. 8, 461–480 (2013).
Google Scholar
Cox, J. et al. Andromeda: a peptide search engine integrated into the MaxQuant environment. J. Proteome Res. 10, 1794–1805 (2011).
Google Scholar
Tyanova, S., Temu, T. & Cox, J. The MaxQuant computational platform for mass spectrometry-based shotgun proteomics. Nat. Protoc. 11, 2301–2319 (2016).
Google Scholar
UniProt Consortium UniProt: a worldwide hub of protein knowledge. Nucleic Acids Res. 47, D506–D515 (2019).
Google Scholar
Tyanova, S. et al. The Perseus computational platform for comprehensive analysis of (prote)omics data. Nat. Methods 13, 731–740 (2016).
Google Scholar
Raudvere, U. et al. g:Profiler: a web server for functional enrichment analysis and conversions of gene lists (2019 update). Nucleic Acids Res. 47, W191–W198 (2019).
Google Scholar
Morpheus (The Broad Institute); https://software.broadinstitute.org/morpheus
Kulkarni, R. U., Wang, C. L. & Bertozzi, C. R. Analyzing nested experimental designs: a user-friendly resampling method to determine experimental significance. PLoS Comput. Biol. 18, e1010061 (2022).
Google Scholar
Perez-Riverol, Y. et al. The PRIDE database at 20 years: 2025 update. Nucleic Acids Res. 53, D543–D553 (2025).
Google Scholar
Leus, N. G. J. et al. HDAC1-3 inhibitor MS-275 enhances IL10 expression in RAW264.7 macrophages and reduces cigarette smoke-induced airway inflammation in mice. Sci. Rep. 7, 45047 (2017).
Google Scholar
Bhat, M. F. et al. Impact of HDAC inhibitors on macrophage polarization to enhance innate immunity against infections. Drug Discov. Today 29, 104193 (2024).
Google Scholar
Leus, N. G. J. et al. HDAC 3-selective inhibitor RGFP966 demonstrates anti-inflammatory properties in RAW 264.7 macrophages and mouse precision-cut lung slices by attenuating NF-κB p65 transcriptional activity. Biochem. Pharmacol. 108, 58–74 (2016).
Google Scholar
Li, X. et al. HDAC inhibition potentiates anti-tumor activity of macrophages and enhances anti-PD-L1-mediated tumor suppression. Oncogene 40, 1836–1850 (2021).
Google Scholar
Guerriero, J. L. et al. Class IIa HDAC inhibition reduces breast tumours and metastases through anti-tumour macrophages. Nature 543, 428–432 (2017).
Google Scholar
Hamaidia, M. et al. Inhibition of EZH2 methyltransferase decreases immunoediting of mesothelioma cells by autologous macrophages through a PD-1-dependent mechanism. JCI Insight 4, e128474 (2019).
Google Scholar
Li, C. et al. EZH2 inhibitors suppress colorectal cancer by regulating macrophage polarization in the tumor microenvironment. Front. Immunol. 13, 857808 (2022).
Google Scholar
Zambuzi, F. A. et al. Decitabine promotes modulation in phenotype and function of monocytes and macrophages that drive immune response regulation. Cells 10, 868 (2021).
Google Scholar
Willemsen, L. et al. DOT1L regulates lipid biosynthesis and inflammatory responses in macrophages and promotes atherosclerotic plaque stability. Cell Rep. 41, 111703 (2022).
Google Scholar
Zhang, Y. et al. Zebularine potentiates anti-tumor immunity by inducing tumor immunogenicity and improving antigen processing through cGAS–STING pathway. Commun. Biol. 7, 587 (2024).
Google Scholar
De Vries, L. C. S. et al. A JAK1 selective kinase inhibitor and tofacitinib affect macrophage activation and function. Inflamm. Bowel Dis. 25, 647–660 (2019).
Google Scholar
Huarte, E. et al. Ruxolitinib, a JAK1/2 inhibitor, ameliorates cytokine storm in experimental models of hyperinflammation syndrome. Front. Pharmacol. 12, 650295 (2021).
Google Scholar
Akcora, B. Ö et al. TG101348, a selective JAK2 antagonist, ameliorates hepatic fibrogenesis in vivo. FASEB J. 33, 9466–9475 (2019).
Google Scholar
Mathew, D. et al. Combined JAK inhibition and PD-1 immunotherapy for non-small cell lung cancer patients. Science 384, eadf1329 (2024).
Google Scholar
Soleimani, M. et al. Covalent JNK inhibitor, JNK-IN-8, suppresses tumor growth in triple-negative breast cancer by activating TFEB- and TFE3-mediated lysosome biogenesis and autophagy. Mol. Cancer Ther. 21, 1547–1560 (2022).
Google Scholar
Chen, H., Liu, N. & Zhuang, S. Macrophages in renal injury, repair, fibrosis following acute kidney injury and targeted therapy. Front. Immunol. 13, 934299 (2022).
Google Scholar
Wang, L. et al. PARP-inhibition reprograms macrophages toward an anti-tumor phenotype. Cell Rep. 41, 111462 (2022).
Google Scholar
Qian, J.-F. et al. Isoproterenol induces MD2 activation by β-AR-cAMP-PKA-ROS signalling axis in cardiomyocytes and macrophages drives inflammatory heart failure. Acta Pharmacol. Sin. 45, 531–544 (2024).
Google Scholar
Busch, L. et al. Lenalidomide enhances MOR202-dependent macrophage-mediated effector functions via the vitamin D pathway. Leukemia 32, 2445–2458 (2018).
Google Scholar
Bogdan, C. & Ding, A. Taxol, a microtubule-stabilizing antineoplastic agent, induces expression of tumor necrosis factor alpha and interleukin-1 in macrophages. J. Leukoc. Biol. 52, 119–121 (1992).
Google Scholar
Martinet, W. et al. Everolimus triggers cytokine release by macrophages: rationale for stents eluting everolimus and a glucocorticoid: rationale for stents eluting everolimus and a glucocorticoid. Arterioscler. Thromb. Vasc. Biol. 32, 1228–1235 (2012).
Google Scholar
Zhou, Q. et al. Carfilzomib modulates tumor microenvironment to potentiate immune checkpoint therapy for cancer. EMBO Mol. Med. 14, e14502 (2022).
Google Scholar
Fang, F. et al. C646 modulates inflammatory response and antibacterial activity of macrophage. Int. Immunopharmacol. 74, 105736 (2019).
Google Scholar
Uramatsu, T. et al. Involvement of apoptosis inhibitor of macrophages in a rat hypertension model with nephrosclerosis: possible mechanisms of action of olmesartan and azelnidipine. Biol. Pharm. Bull. 36, 1271–1277 (2013).
Google Scholar
Morsali, D. et al. Safinamide and flecainide protect axons and reduce microglial activation in models of multiple sclerosis. Brain 136, 1067–1082 (2013).
Google Scholar
Wilson, A. K., Takai, A., Ruegg, J. C. & de Lanerolle, P. Okadaic acid, a phosphatase inhibitor, decreases macrophage motility. Am. J. Physiol. 260, L105–L112 (1991).
Google Scholar
Schmidt, N. & Gans, E. H. Tretinoin: a review of its anti-inflammatory properties in the treatment of acne. J. Clin. Aesthet. Dermatol. 4, 22–29 (2011).
Google Scholar
Cui, S.-N. et al. Trichostatin A modulates the macrophage phenotype by enhancing autophagy to reduce inflammation during polymicrobial sepsis. Int. Immunopharmacol. 77, 105973 (2019).
Google Scholar
Tseng, W.-C., Tsai, M.-T., Chen, N.-J. & Tarng, D.-C. Trichostatin A alleviates renal interstitial fibrosis through modulation of the M2 macrophage subpopulation. Int. J. Mol. Sci. 21, 5966 (2020).
Google Scholar
Han, H., Kang, J.-K., Ahn, K. J. & Hyun, C.-G. DMSO alleviates LPS-induced inflammatory responses in RAW264.7 macrophages by inhibiting NF-κB and MAPK activation. BioChem (Basel) 3, 91–101 (2023).
Google Scholar
Lee, S. J., Lee, S. H., Koh, A. & Kim, K. W. EGF-conditioned M1 macrophages Convey reduced inflammation into corneal endothelial cells through exosomes. Heliyon 10, e26800 (2024).
Google Scholar
Shabani, M. et al. Resveratrol alleviates obesity-induced skeletal muscle inflammation via decreasing M1 macrophage polarization and increasing the regulatory T cell population. Sci. Rep. 10, 3791 (2020).
Google Scholar
O’Neil, J. D. et al. Dexamethasone impairs the expression of antimicrobial mediators in lipopolysaccharide-activated primary macrophages by inhibiting both expression and function of interferon β. Front. Immunol. 14, 1190261 (2023).
Google Scholar
Yoshino, T. et al. Immunosuppressive effects of tacrolimus on macrophages ameliorate experimental colitis. Inflamm. Bowel Dis. 16, 2022–2033 (2010).
Google Scholar
Joshi, H. et al. The pharmacological implications of flavopiridol: an updated overview. Molecules 28, 7530 (2023).
Google Scholar
Iqbal, N. & Iqbal, N. Imatinib: a breakthrough of targeted therapy in cancer. Chemother. Res. Pract. 2014, 357027 (2014).
Google Scholar
Tousif, S. et al. Ponatinib drives cardiotoxicity by S100A8/A9-NLRP3-IL-1β mediated inflammation. Circ. Res. 132, 267–289 (2023).
Google Scholar
Brownlow, N., Mol, C., Hayford, C., Ghaem-Maghami, S. & Dibb, N. J. Dasatinib is a potent inhibitor of tumour-associated macrophages, osteoclasts and the FMS receptor. Leukemia 23, 590–594 (2009).
Google Scholar
Murphy, D. A. et al. Angiogenic and immunomodulatory biomarkers in axitinib-treated patients with advanced renal cell carcinoma. Future Oncol. 16, 1199–1210 (2020).
Google Scholar
Tariq, M. et al. Macrophages M2 polarization is involved in lapatinib-mediated chemopreventive effects in the lung cancer. Biomed. Pharmacother. 161, 114527 (2023).
Google Scholar
Blay, J.-Y. & von Mehren, M. Nilotinib: a novel, selective tyrosine kinase inhibitor. Semin. Oncol. 38, S3–S9 (2011).
Google Scholar
Du, S.-L., Yuan, X., Zhan, S., Tang, L.-J. & Tong, C.-Y. Trametinib, a novel MEK kinase inhibitor, suppresses lipopolysaccharide-induced tumor necrosis factor (TNF)-α production and endotoxin shock. Biochem. Biophys. Res. Commun. 458, 667–673 (2015).
Google Scholar
Hage, C. et al. Sorafenib induces pyroptosis in macrophages and triggers natural killer cell-mediated cytotoxicity against hepatocellular carcinoma. Hepatology 70, 1280–1297 (2019).
Google Scholar
De, M. et al. MEK1/2 inhibition decreases pro-inflammatory responses in macrophages from people with cystic fibrosis and mitigates severity of illness in experimental murine methicillin-resistant Staphylococcus aureus infection. Front. Cell. Infect. Microbiol. 14, 1275940 (2024).
Google Scholar
Fu, W. et al. Epigenetic modulation of type-1 diabetes via a dual effect on pancreatic macrophages and β cells. Elife 3, e04631 (2014).
Google Scholar
Hong, H. & Benveniste, E. N. The immune regulatory role of protein kinase CK2 and its implications for treatment of cancer. Biomedicines 9, 1932 (2021).
Google Scholar
Leitch, A. E., Haslett, C. & Rossi, A. G. Cyclin-dependent kinase inhibitor drugs as potential novel anti-inflammatory and pro-resolution agents. Br. J. Pharmacol. 158, 1004–1016 (2009).
Google Scholar
Sun, M. et al. Vemurafenib inhibits necroptosis in normal and pathological conditions as a RIPK1 antagonist. Cell Death Dis. 14, 555 (2023).
Google Scholar
Doran, A. C. et al. CAMKIIγ suppresses an efferocytosis pathway in macrophages and promotes atherosclerotic plaque necrosis. J. Clin. Invest. 127, 4075–4089 (2017).
Google Scholar
Al Kindi, H. et al. Sustained release of milrinone delivered via microparticles in a rodent model of myocardial infarction. J. Thorac. Cardiovasc. Surg. 148, 2316–2323 (2014).
Google Scholar
Tariq, M. et al. Gefitinib inhibits M2-like polarization of tumor-associated macrophages in Lewis lung cancer by targeting the STAT6 signaling pathway. Acta Pharmacol. Sin. 38, 1501–1511 (2017).
Google Scholar
Wolf, A. M. et al. The kinase inhibitor imatinib mesylate inhibits TNF-α production in vitro and prevents TNF-dependent acute hepatic inflammation. Proc. Natl Acad. Sci. USA 102, 13622–13627 (2005).
Google Scholar
Sellon, D. C., Walker, K. M., Russell, K. E., Perry, S. T. & Fuller, F. J. Phorbol ester stimulation of equine macrophage cultures alters expression of equine infectious anemia virus. Vet. Microbiol. 52, 209–221 (1996).
Google Scholar
Hill, A. A. et al. Activation of NF-κB drives the enhanced survival of adipose tissue macrophages in an obesogenic environment. Mol. Metab. 4, 665–677 (2015).
Google Scholar
Frankenberg, T., Kirschnek, S., Häcker, H. & Häcker, G. Phagocytosis-induced apoptosis of macrophages is linked to uptake, killing and degradation of bacteria. Eur. J. Immunol. 38, 204–215 (2008).
Google Scholar
Matsuda, T. et al. Cabozantinib prevents the progression of metabolic dysfunction-associated steatohepatitis by inhibiting the activation of hepatic stellate cell and macrophage and attenuating angiogenic activity. Heliyon 10, e38647 (2024).
Google Scholar




