Neoadjuvant anti-programmed cell death 1 (PD-1) immunochemotherapy has shown promising efficiency in the treatment of early-stage non-small-cell lung cancer (NSCLC), but it has not consistently yielded durable responses. Biomarkers for the prediction of efficacy are warranted.
We performed shotgun metagenomic and plasma/faecal metabolomic studies in 44 NSCLC patients who underwent neoadjuvant tislelizumab plus platinum-based doublet chemotherapy. Samples were collected at baseline and before surgical resection, and the major pathologic response (MPR) was evaluated.
MPR patients showed a significantly higher gut-microbial alpha diversity, an enrichment of Ruminococcaceae, Lachnospiraceae and Clostridiales species, and an increased plasma level of tryptophan metabolites at baseline. On the contrary, non-MPR patients were characterized by enrichment of Prevotella species in faecal samples and higher plasma levels of linoleic acid metabolites. A high predictive accuracy was achieved using a small panel of differential microbial (Clostridium sp. M62/1 and Eisenbergiella tayi) or metabolomic features (linoleic acid, oxindole-3-acetic acid and quinolinic acid) with AUCs > .85.
The baseline characteristics of the gut microbiota and plasma metabolites could provide early predictions of the response to neoadjuvant anti-PD-1 immunochemotherapy.
NCT05244837.
Pseudouridine synthases (PUS) have been implicated in various cancers, yet their roles in pancreatic cancer immunity remain unclear. Through integrative multi-omics analyses combining genomics, transcriptomics, and clinical datasets, we evaluated associations between PUS family genes and oncogenic features, including tumour microenvironment scores, immune infiltration, cancer stemness, and prognosis. Among them, PUS7 and PUS3 showed the strongest correlations with tumour-promoting phenotypes, with high PUS7 expression in PDAC predicting poor overall survival. Functional assays revealed that PUS7 overexpression markedly enhanced PDAC cell proliferation, migration, and invasion. Transcriptomic profiling demonstrated that PUS7 promotes neutrophil extracellular traps formation, identifying it as a key regulator of NET-mediated immune modulation. Single-cell RNA sequencing of orthotopic mouse models showed PUS7 overexpression reduced macrophage infiltration and skewed macrophage polarization towards the M2 phenotype while suppressing M1 polarization. We found that PUS7 reshapes the PDAC immune landscape primarily by inducing NETs, which drive macrophage polarization from M1 to M2, fostering immune suppression and tumour progression. The PUS7–NET–M2/M1 axis thus represents a novel mechanism of PDAC pathogenesis and a potential therapeutic target in this lethal malignancy.
Triple-negative breast cancer (TNBC), marked by profound immunosuppressive complexity, poses a critical challenge in therapy due to the absence of hormone receptors in its phenotype, making it unavailable for conventional therapies. The stimulator of interferon genes (STING) pathway is emerging as critical pathway translating the immunogenic ‘cold’ TNBC tumour into ‘hot’ one, thereby improving the responsiveness to immune checkpoint blockade (ICB). However, the clinical translation is still hindered by insufficient cytosolic delivery, rapid systemic degradation and tumour microenvironment-induced metabolic inactivation. This review outlines the recent advances in STING-mediated nanoparticle delivery with special emphasis on biomimetic, Trojan horse logic gate, manganese-based and redox-responsive stimuli delivery systems. Mechanistically, it integrates immune activation by ferroptosis, cuproptosis and mitochondrial DNA disruption. They synergise the amplification of type 1 interferon with dendritic cell maturation, potentiating antitumour immunogenesis. Notably, the combination with ICBs will further amplify the therapeutic potential of nanoparticles. Convergence of immunology and targeted therapies with nanoparticles opens new array for TNBC treatment. The review visualizes the clinical translation of mind maps into clinical reality, activating the innate immunity.
Immune checkpoint blockade (ICB) has revolutionized tumour therapy by relieving immunosuppression and restoring effector T cell cytotoxicity. However, its clinical utility is constrained by low response rates and acquired resistance. Tumour-associated neutrophils (TANs), key players in tumour immunoregulation, have emerged as critical mediators of ICB responsiveness and resistance, highlighting the therapeutic potential of combining TAN-targeted strategies with immune checkpoint inhibitors (ICIs). This review systematically synthesizes current knowledge of neutrophils in ICB resistance from several dimensions: (1) clinical indicators of neutrophils, such as the neutrophil-to-lymphocyte ratio (NLR) and tissue TANs abundance, as predictors of ICI response and patients prognosis; (2) multifaceted TAN-involved resistance mechanisms, including direct T cell inhibition, antigen presentation impairment, function modulation of other immune cells, promotion of tumour angiogenesis, and elevation of tumour mutation burden (TMB); (3) combination therapeutic strategies targeting TAN generation/ exhaustion, recruitment, phenotypic polarization, activation, proangiogenic functions, and neutrophil extracellular traps (NETs), along with progress in related clinical trials. Combinatorial approaches integrating TAN-targeted therapies with ICIs hold substantial promise for overcoming resistance by reshaping the immune microenvironment. Elucidating neutrophil-mediated resistance mechanisms and optimizing combination strategies will pave the way for precision tumour immunotherapy.
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：