Pancreatic Ductal Adenocarcinoma

Despite apparently favorable pathological staging and adjuvant FOLFIRINOX chemotherapy, the patient developed early biochemical progression with rapidly rising carbohydrate antigen 19-9 (CA 19-9) levels, followed by widespread metastatic dissemination involving the liver, lung, spine, skeletal muscle, and multiple visceral sites...This case highlights the limitations of anatomical staging in PDAC and emphasizes the prognostic importance of tumor biology, including KRAS mutation status, lymphovascular invasion, and perineural invasion. It also demonstrates the potential limitations of CA 19-9 as a solitary marker of treatment response in biologically aggressive disease.

Functional blockade of CCL22 reduced TGF-β secretion by rKPC apCAF-induced Tregs, supporting a mechanistic role for this pathway in fostering an immunosuppressive TME. These findings position apCAFs as regulators of CD4 T-cell antitumor immunity in PDAC and suggest that modulating apCAF-T-cell interactions could offer strategies to enhance immunotherapy efficacy.

These data provide a comprehensive overview on the prevalence on homozygous and heterozygous 9p21 deletions in cancer and demonstrate that different cancer types markedly differ in their ratio of homozygous/heterozygous 9p21 deletions. The strong concordance between homozygous 9p21 deletions and absent MTAP immunostaining highlights the effectiveness of immunohistochemistry in detecting MTAP deficiency.

Neoadjuvant NALIRIFOX is a safe and active regimen in R/BR PDAC with a low post-operative complication rate, high treatment completion and R0 resection rates, and meaningful clinical responses. These findings support further investigation of NALIRIFOX as part of a total neoadjuvant therapy (TNT) approach in PDAC. [ClinicalTrials.gov identifier: NCT03483038].

Pharmacological interventions, including HDAC inhibitors, JAK/STAT3 inhibitors, metformin, and anti-inflammatory agents, show potential in preventing or reversing ADM. Understanding the complex molecular, cellular, and environmental regulation of ADM provides critical insights into pancreatic regeneration and early tumorigenesis and offers a framework for developing targeted strategies for the prevention and treatment of pancreatitis and PDAC.

P1, N=500, Recruiting, MediLink Therapeutics (Suzhou) Co., Ltd. | N=155 --> 500 | Trial completion date: Apr 2029 --> Jun 2031 | Trial primary completion date: Apr 2027 --> Jun 2031

Although inhibition of autophagy with hydroxychloroquine and related lysosomal inhibitors has provided proof of concept, their limited specificity has motivated the development of more selective approaches, such as Unc-51-like autophagy activating kinase 1 (ULK1) inhibitors and selective autophagy receptor-directed strategies. Emerging combination regimens that integrate autophagy blockade with KRAS/extracellular signal-regulated kinase (ERK) pathway inhibition, metabolic stress, or immune checkpoint blockade may help overcome chemoresistance and enhance anti-tumor immunity. Together, these advances underscore the therapeutic promise of targeting metabolic plasticity and autophagy in PDAC and lay the groundwork for rational next-generation combination strategies.

Beyond cutting off nutrient supply to malignant cells, the nanomodulator also demonstrates the capacity to remodel the TME and reactivate antitumor immunity, thereby eliciting enhanced tumor suppression. Through the ratio-precise codelivery system, this study discussed the possibility of translating in vitro validated synergistic metabolism modulation into a controllable in vivo combination therapy modality, providing a generalizable strategy for metabolism modulating cancer therapy and the rational design of precision drug delivery systems.

Furthermore, by systematically separating expression sources, our clinical validation established that tumor-derived CD52 is a prognostic indicator of poor patient survival. These findings characterize CD52 as a critical, tumor-intrinsic driver of PDAC progression, highlighting its value as a prognostic biomarker and a therapy target in combination with immune checkpoint blockade to overcome innate therapeutic resistance in PDAC.

SIGLEC12 is frequently upregulated in PDAC and predicts poor prognosis. Notably, our exploratory findings suggest that SIGLEC12 may modify the prognostic effect of CA19‑9 and the therapeutic benefit of ACT. These findings position SIGLEC12 as a promising prognostic biomarker and novel therapeutic target in PDAC, with potential for further roles in refining risk stratification and guiding personalized treatment decisions.

Serum TIMP-1 is associated with malignant and metastatic pancreatic disease and reflects a more aggressive tumor phenotype in patients with established pancreatic cancer. While the observed differences are modest and limit its applicability as a stand-alone diagnostic or screening biomarker, TIMP-1 may provide clinically relevant information regarding metastatic status and could contribute to prognostic stratification or multimarker approaches in pancreatic cancer.

Patient-derived small extracellular vesicles induced similar but less pronounced effects. Overall, pancreatic ductal adenocarcinoma-derived small extracellular vesicles induced early hepatic microenvironmental remodelling, supporting a potential role for tumour-liver crosstalk in pre-metastatic niche-associated processes, highlighting tumour-liver crosstalk as a potential therapeutic target.