tolterodine (Detrol LA / Detrusitol Neo / Detrusitol Retard)

Siglec-15 binds mucin-domain glycoproteins with extended glycans and marks an osteoclast-like, matrix remodeling myeloid state in human tumors.

Derosiers Nohelly N, Aguilar William W, Lewis Hyeon-Gyu S HS, MacDonald Morgann M et al.

Siglec-15 has emerged as a therapeutic target in cancer, yet the glycan determinants and protein scaffolds that mediate engagement between Siglec-15-expressing myeloid cells and tumor cells remain incompletely defined. Here, we investigated the molecular basis of Siglec-15 recognition of cancer cells and examined transcriptional as well as functional programs associated with Siglec-15 expression in tumor-associated myeloid populations. Using immunoprecipitation-mass spectrometry in the pancreatic cancer cell line AsPC-1, we identified multiple mucin-domain glycoproteins enriched in Siglec-15 pulldowns. Disruption of glycan structures demonstrated that both complex N-glycans and extended mucin-type O-glycans contribute to optimal Siglec-15 binding. To define the myeloid population associated with Siglec-15 in human tumors, we interrogated publicly available single-cell RNA sequencing datasets and found that SIGLEC15 expression is enriched within a subset of tumor-associated myeloid cells exhibiting transcriptional features linked to osteoclast differentiation and extracellular matrix remodeling. Finally, in a THP-1 coculture model, Siglec-15 was further associated with DAP12-dependent tumor-induced expression of the osteoclast markers ACP5 and MMP9, together with increased release of IL-1β and IL-6. Collectively, these findings identify glycan and glycoprotein features that support Siglec-15 binding to malignant cells and associate SIGLEC15 expression with osteoclast-like and matrix-remodeling myeloid programs in human cancers, providing a framework for mechanistic studies of this glyco-immune checkpoint.

Lymph node fine-tuning FcγR signaling boosts anti-PD-1 therapy.

Guérin Marion V MV, Ruggiu Mathilde M, Feldmann Lea C LC, Corre Béatrice B et al.

Anti-PD-1 monoclonal antibody (mAb) therapy promotes the emergence of new T cell clonotypes within tumors, suggesting de novo priming in the periphery. Yet, the mechanisms that mobilize these additional T cells remain poorly defined. We investigated the impact of anti-PD-1 mAbs on circulating T cell dynamics and their recruitment into tumor-draining lymph nodes (TDLNs) using multiple transgenic mouse models, including FcγR-deficient and type I interferon receptor-deficient mice. To dissect the role of FcγR engagement, we compared an Fc-silent anti-PD-1 LALAPG variant alongside conventional anti-PD-1 antibodies, and further extended our study to an additional immune checkpoint inhibitor for comparison. These approaches were complemented by experiments in FcγR-humanized mice using a human IgG4 anti-PD-1 mAb. In parallel, the effects of the therapeutic IgG4 antibody nivolumab were evaluated in human cell-based assays using dynamic imaging. Here, we demonstrate that anti-PD-1 mAbs promote the recruitment of circulating T cells into TDLNs, resulting in an expanded anti-tumor T cell response. This influx was part of a general reactive lymphadenopathy that required FcγR engagement and type I IFN production, leading to a burst of chemokine release. These results were extended to FcgR-humanized mice treated with a human IgG4 variant of the anti-PD-1 mAb and were similarly observed with another immune checkpoint inhibitor, anti-TIM-3, broadening this mechanism as a major one during checkpoint blockade in the LN. Our results reveal a previously unrecognized role for low to moderate FcγR engagement in TDLNs, which amplifies the anti-tumor T-cell response elicited during anti-PD-1 therapy.

Erratum regarding extended PDF errors in previously published articles.

Directional Concerted Proton-Electron Transfer in COFs for Efficient Photocatalytic H2O2 Production.

Wang Shi S, Jiang Xinzhu X, Yang Hanpei H, Kang Xudong X et al.

Photocatalytic two-electron oxygen reduction reaction (2e- ORR) offers a sustainable route for green H2O2 synthesis. However, its efficiency is fundamentally constrained by the kinetic mismatch between proton transfer and electron migration across heterogeneous interfaces. Inspired by concerted proton-electron translocation in natural hydrogenases, we report a catechol-triazine donor-acceptor (D-A) covalent organic framework, 2,3-Dhta-Tt, for directional concerted proton-electron transfer (DCPET) during photocatalytic H2O2 production. The intrinsic built-in electric field, combined with a catechol-derived dynamic proton-relay network, aligns proton and electron fluxes and establishes a periodic co-transport channel toward triazine acceptor sites. At the molecular level, the catechol donor units dominate the highest occupied molecular orbital (HOMO), acting simultaneously as photoexcitation centers and initial proton-release sites, thereby synchronizing proton delivery with electron migration. This vectorial coupling lowers the activation barrier for O─O hydrogenation and promotes highly selective 2e- ORR, affording an H2O2 production rate of 27.22 mmol g-1 h-1 in pure water. The framework also exhibits proton conductivity of 6.09 × 10-5 S cm-1 and an extended excited-state lifetime of 94.45 ps. Isotope labeling, operando spectroscopy, and DFT calculations support a proton-cycling process and directional proton/electron participation. This work advances heterogeneous photocatalyst design beyond conventional PCET cooperativity.