Idris Vruzhaj

Background: Pancreatic ductal adenocarcinoma (PDAC) exhibits marked resistance to immunotherapy. Beyond its characteristically low tumor mutational burden, post-translational modifications (PTMs) remodel the immunopeptidome and promote immune escape through reversible, enzyme-driven programs. Subject Matter: We synthesize evidence that aberrant glycosylation, O-GlcNAcylation, phosphorylation, and citrullination constitute core determinants of antigen visibility operating within spatially discrete tumor niches and a desmoplastic stroma. In hypoxic regions, HIF-linked hexosamine metabolism and OGT activity stabilize immune checkpoints and attenuate antigen processing; at tumor margins, sialylated mucins engage inhibitory Siglec receptors on innate and adaptive lymphocytes; within the stroma, PAD4-dependent NET formation enforces T cell exclusion. We also delineate technical barriers to discovering PTM antigens labile chemistry, low stoichiometry, and method-embedded biases and outline practical solutions: ETD/EThcD/AI-ETD fragmentation, PTM-aware database searching and machine-learning models, and autologous validation in patient-derived organoid–T cell co-cultures. Finally, we highlight therapeutic strategies that either immunize against PTM neoepitopes or inhibit PTM machinery (e.g., PAD4, OGT, ST6GAL1), with stromal remodeling as an enabling adjunct. Conclusions: PTM biology, spatial omics, and patient sample models can uncover targetable niches and speed up PDAC vaccination, TCR, and enzyme-directed treatment development.

Aging is characterized by a progressive deterioration in physiological function and an increased susceptibility to age-related diseases, such as cancer. Monoclonal antibodies (mAbs) constitute a novel therapeutic approach aimed at addressing aging mechanisms such as cellular senescence, inflammaging, and immunosenescence. This text presents an overview of mAb methods aimed at the markers of aging and their potential application in cancer treatment. The mAbs can be categorized into senolytics, senescence-associated secretory phenotype (SASP) neutralizers, and immune checkpoint inhibitors, each targeting fewer aging-related pathways relevant to cancer therapeutic enhancement than the last. Translating promising preclinical evidence into enhanced efficacy and safety in cancer therapy presents challenges, particularly in older populations. This study examines the therapeutic efficacy of mAbs in the treatment of cancer and age-related disorders, focusing on their current and future roles in oncology practice.

Background and Objectives: The administration of oral vaccines offers a potential strategy for cancer immunotherapy; yet, the development of effective platforms continues to pose a difficulty. This study examines Escherichia coli Nissle 1917 (EcN) as a microbial vector for the precise delivery of Glypican-1 (GPC1), a tumor-associated antigen significantly overexpressed in pancreatic ductal adenocarcinoma (PDAC).To evaluate the effectiveness of EcN as a vector for the delivery of GPC1 and assess its potential as an oral vaccination platform for cancer immunotherapy. Materials and Methods: EcN was genetically modified to produce a GPC1-flagellin fusion protein (GPC1-FL) to augment antigen immunogenicity. The expression and stability of GPC1 were confirmed in modified PANC02 cells using Western blot and flow cytometry, indicating that GPC1 expression did not influence tumor cell growth. A mouse model was employed to test immunogenicity post-oral delivery, measuring systemic IgG, IL-10, IL-2, and IFN-γ levels to indicate immune activation. Results: Oral immunization with EcN GPC1-FL elicited a robust systemic immune response, demonstrated by markedly increased levels of IgG and IL-10. IL-2 and IFN-γ concentrations were elevated in vaccinated mice relative to controls; however, the differences lacked statistical significance. Western blot examination of fecal samples verified consistent antigen expression in the gastrointestinal tract, indicating effective bacterial colonization and antigen retention. No detrimental impacts were noted, hence substantiating the safety of this methodology. Conclusions: These findings confirm EcN as a feasible and patient-friendly oral vaccination platform for cancer immunotherapy. The effective production of GPC1 in tumor cells, along with continuous antigen delivery and immune activation, underscores the promise of this approach for PDAC and other cancers. This study promotes microbial-based antigen delivery as a scalable, non-invasive substitute for traditional vaccine platforms.

Cancer vaccines, a burgeoning strategy in cancer treatment, are exploring innovative administration routes to enhance patient and medical staff experiences, as well as immunological outcomes. Among these, oral administration has surfaced as a particularly noteworthy approach, which is attributed to its capacity to ignite both humoral and cellular immune responses at systemic and mucosal tiers, thereby potentially bolstering vaccine efficacy comprehensively and durably. Notwithstanding this, the deployment of vaccines through the oral route in a clinical context is impeded by multifaceted challenges, predominantly stemming from the intricacy of orchestrating effective oral immunogenicity and necessitating strategic navigation through gastrointestinal barriers. Based on the immunogenicity of the gastrointestinal tract, this review critically analyses the challenges and recent advances and provides insights into the future development of oral cancer vaccines.