Hui Dai

Peripheral T cell profiles reflect antitumour immunity, yet systemic immune shifts often remain confounded by demographic factors. This study aimed to delineate true tumour‐driven T cell alterations in lung cancer. We analysed peripheral blood from 121 lung cancer patients and strictly age‐ and sex‐matched healthy controls using multiparametric flow cytometry, corroborated by human lung cancer spatial transcriptomics (ST). Following demographic standardisation, patients exhibited a systemic T cell priming blockade, characterised by significantly accumulated naïve T cells and depleted effector memory T cells (CD4 ⁺ p < 0.01; CD8 ⁺ p < 0.0001). Conversely, Th17.1 cells and immune checkpoints (e.g., PD‐1, CTLA‐4) were robustly elevated. Crucially, ST validated a striking intratumoural spatial accumulation of Th17.1 cells. We conclude that the peripheral expansion of Th17.1 cells is a genuine tumour‐driven event that faithfully mirrors local tumour microenvironment remodelling and potential Tertiary Lymphoid Structure (TLS) neogenesis. This positions peripheral Th17.1 profiling as a valuable, noninvasive biomarker for evaluating systemic immunosuppression and guiding personalised immunotherapy.

Realizing the therapeutic potential of antibodies requires simultaneously optimizing multiple properties, such as antigen-binding specificity, viscosity, clearance and immunogenicity. However, existing methods used for this task are time consuming and resource intensive, often struggling to balance these properties. Here we propose DualGPT-AB, a dual-stage conditional generative pre-trained transformer (GPT) framework for therapeutic antibody design. DualGPT-AB leverages a conditional GPT to model sequence–property relationships by representing the desired properties as learnable embeddings, while incorporating a reinforcement learning strategy to promote antibody sequence exploration and improve optimization efficiency. Computational experiments show that DualGPT-AB is capable of generating antibody heavy chain complementarity-determining region 3 (CDRH3) sequences fulfilling multiple desired properties. Notably, 8 out of 100 randomly selected antibodies from our designed candidate library exhibit excellent HER2-binding affinities. Wet-laboratory validation confirms that DualGPT-AB identifies antibodies with enhanced tumoricidal activity compared with Herceptin, a widely used antibody drug for treating HER2-positive cancers. Overall, DualGPT-AB is a promising approach for advancing artificial intelligence-driven therapeutic antibody development.

Supplementary figures and tables.

Supplementary figures and tables.

Supplementary figures and tables.

Elevated IgG expression in cancer cells has been implicated in exacerbated malignancy and poor clinical prognosis. Accumulating evidence indicates that a nonconventional sialylation modification is critical for the function of cancer-derived IgG, indicating the need for a better understanding of the regulatory mechanisms that control the expression and function of sialylated cancer IgG (SIA-cIgG). Here, we conducted genome-wide CRISPR activation screening and identified OCT4 and SOX2 as the key factors that promote SIA-cIgG expression. Functional investigation revealed that SIA-cIgG reciprocally stimulated SOX2 by activating the c-Met/Akt/Erk signaling axis, constituting a self-propagating loop of SIA-cIgG/c-Met/SOX2/SIA-cIgG signaling. This signaling loop was highly active in stem-like cells from many epithelial cancers and was crucial for cancer stemness in vitro and in vivo. Notably, the monoclonal antibody RP215, which specifically recognizes the Asn162 sialylation-related epitope on SIA-cIgG, effectively blocked the SIA-cIgG-driven signaling loop. Furthermore, RP215 significantly inhibited lung cancer cell stemness and tumor growth in a patient-derived xenograft model. In conclusion, these findings revealed a self-propagating c-Met/SOX2/SIA-cIgG signaling loop that promotes cancer stemness, identifying novel therapeutic strategies for cancer treatment.

Skin is the most prominent tissue and organ, as well as the first line of defence, of the body. Because it is situated on the body's surface, it is constantly exposed to microbial, chemical, and physical factors such as mechanical stimulation. Therefore, skin has evolved substantial immune defences, regenerative ability, and anti-injury capacity. Epidermal cells produce antibacterial peptides that play a role in immune defence under physiological conditions. Additionally, IgG or IgA in the skin also participates in local anti-infective immunity. However, based on the classical theory of immunology, Ig can only be produced by B cells which should be derived from local B cells. This year, thanks to the discovery of Ig derived from non B cells (non B-Ig), Ig has also been found to be expressed in epidermal cells and contributes to immune defence. Epidermal cell-derived IgG and IgA have been demonstrated to have potential antibody activity by binding to pathogens. However, these epidermal cell-derived Igs show different microbial binding characteristics. For instance, IgG binds to Staphylococcus aureus and IgA binds to Staphylococcus epidermidis. Epidermal cells producing IgG and IgA may serve as an effective defense mechanism alongside B cells, providing a novel insight into skin immunity.

Glycans, either alone or in complex with glycan-binding proteins, are essential structures that can regulate cell biology by mediating protein stability or receptor dimerization under physiological and pathological conditions. Certain glycans are ligands for lectins, which are carbohydrate-specific receptors. Bone is a complex tissue that provides mechanical support for muscles and joints, and the regulation of bone mass in mammals is governed by complex interplay between bone-forming cells, called osteoblasts, and bone-resorbing cells, called osteoclasts. Bone erosion occurs when bone resorption notably exceeds bone formation. Osteoclasts may be activated during cancer, leading to a range of symptoms, including bone pain, fracture, and spinal cord compression. Our understanding of the role of protein glycosylation in cells and tissues involved in osteoclastogenesis suggests that glycosylation-based treatments can be used in the management of diseases. The aims of this review are to clarify the process of bone resorption and investigate the signaling pathways mediated by glycosylation and their roles in osteoclast biology. Moreover, we aim to outline how the lessons learned about these approaches are paving the way for future glycobiology-focused therapeutics.