CCR6 (C-C Motif Chemokine Receptor 6)

Moreover, multiple proteins in PBMCs, distinct from the irAE-predicting biomarkers, exhibited differential expression levels corresponding to the differential responses to the PD-1 inhibitors. Via multiple independent cohorts, our study revealed crucial roles of CXCR3 and CCR6 in PD-1-induced irAEs, provided potential circulating biomarkers associated with toxicity and responses of PD-1 inhibitors and further sculptured the landscape of immune cell heterogeneity via focusing on PBMC subpopulations.

Therapeutic strategies targeting the CCL20-CCR6 axis aim to balance its protective immune-enhancing effects with its pro-inflammatory risks, including developing receptor antagonists to mitigate excessive inflammation and leveraging its chemotactic properties to enhance vaccine efficacy. By bridging basic immunology with translational research, this review provides a comprehensive framework for understanding CCL20 in infectious diseases, offering critical insights for developing precision therapies that harness its dual functions while minimizing collateral damage.

Both BCMA and CD307e were more highly expressed on BM plasma-cells than CTPCs. This study is among the first to provide a comprehensive phenotypic characterisation of CD56+ CTPCs across the MM spectrum, including checkpoint and chemokine receptors, treated disease cases, and paired BM samples for NDMM.

Together, our findings define IA-irAE as a disease with certain immunological features distinctive from RA, representing a potentially T cell-driven, autoantibody-independent autoimmunity. These results offer insights into immune tolerance breakdown and therapeutic targeting in irAEs.

Intratumoral Th7R and Tpex associate with improved response to neoadjuvant PD-1 blockade therapy. These results suggest that Th7R cells act as partners of Tpex to sustain antitumor T-cell immunity.

Focusing on these axes provides mechanistic insights, highlights potential therapeutic targets, and identifies predictive biomarkers. Strategies targeting the chemokine-chemokine receptor axes, including selective receptor blockade, combination with immune checkpoint inhibitors, and omics-based approaches to resolve Treg heterogeneity, offer avenues to reprogram the immunosuppressive TME and enhance antitumor immunity.

Barrier-matched strategies include T-cell redirection (PSMA/STEAP1 engagers, bispecifics, CAR-T) and combinations that heat or modulate myeloid cells. Treating immune heterogeneity as a clinical variable enables durable immunotherapy in PCa.

We further detail past and ongoing therapeutic efforts and trials addressing these axes in both PDAC and relevant non-PDAC settings via several small-molecule antagonists and monoclonal antibodies: BMS-813160, Maraviroc, Leronlimab, FLX475, PF-07054894, IDOR- 1117-2520, and CAP-100. Despite continuous advances in the field, the current body of evidence remains limited and presents significant research gaps in areas such as spatial profiling, stage-specific analyses, and general mechanistic validation in PDAC-specific settings. Addressing these shortcomings will be key to developing a more comprehensive knowledge of the field and improving future therapeutic strategies to overcome PDAC.

Targeting HSPB1 exerts dual anti-tumor effects: it directly suppresses neoplastic proliferation and simultaneously alleviates Treg-mediated immunosuppression within the tumor microenvironment.

Furthermore, CCR6 inhibition potentiated the efficacy of anti-PD1 immune checkpoint blockade. Taken together, our data demonstrate that tumor cell-derived CCL20 shapes an immunosuppressive microenvironment in pancreatic cancer by recruiting CCR6+ Tregs, suggesting that targeting the CCL20-CCR6 axis offers a promising therapeutic strategy, particularly when combined with immune checkpoint blockade.