Fecal proteomics has gained increased prominence in recent years. It can provide insights into the diagnosis and surveillance of many bowel diseases by both identifying potential biomarkers in stool samples and helping identify disease-related pathways. Fecal proteomics has already shown its potential for the discovery and validation of biomarkers for colorectal cancer screening, and the analysis of fecal microbiota by MALDI-MS for the diagnosis of a range of bowel diseases is gaining clinical acceptance. Areas covered: Based on a comprehensive analysis of the current literature, we introduce the range of sensitive and specific proteomics methods which comprise the current 'Proteomics Toolbox', explain how the integration of fecal proteomics with data processing/bioinformatics has been used for the identification of potential biomarkers for both CRC and other gut-related pathologies and analysis of the fecal microbiome, outline some of the current fecal assays in current clinical practice and introduce the concept of personalised medicine which these technologies will help inform. Expert commentary: Integration of fecal proteomics with other proteomics and genomics strategies as well as bioinformatics is paving the way towards personalised medicine, which will bring with it improved global healthcare.

As we move from a discovery to a translational phase in proteomics, with a focus on developing validated clinical assays to assist personalized medicine, there is a growing need for strong bidirectional interactions with the clinical pathology community. Thus, while on one hand the proteomics community will provide candidate biomarkers to assist in diagnosis, prognosis, surveillance, identification of individualized patient medication, and development and validation of new assays for diagnostic use, on the other the pathology community will assist with specific tissue identification and selection (e.g. laser capture microdissection, tissue sections for MS imaging), biobanking, validation of emerging automated histopathology techniques, preparation and classification of relevant patient medical reports, and assisting with the optimization of experimental design for clinical trials. Areas covered: Here we discuss these topics with a particular emphasis on recent publications and relevant initiatives and outline some of the hurdles that still remain for personalized medicine. Expert commentary: It is clear that effective crosstalk between the proteomics and pathology communities will greatly accelerate crossover of candidate biomarkers to personalized medicine, which will have significant benefits not only for patient wellbeing, but also the global healthcare budget. However, analysis of the big data generated may become rate-limiting.

Therapy-induced senescence (TIS) is common in tumor cells treated with poly (ADP-ribose) polymerase inhibitors (PARPis), and can serve as a promising target for improving PARPi efficacy. However, whether stromal components within the tumor microenvironment undergo TIS caused by PARPi and contribute to consequential treatment failure remain unclear. We previously revealed that PARPi triggered a senescence-like secretory phenotype in stromal fibroblasts. Here, we further explored PARPi-induced senescence in the stroma, its contribution to PARPi resistance, and opportunities to leverage stromal TIS for improved PARPi sensitivity. In this study, we demonstrated that tumor tissues from patients treated with neoadjuvant PARPi showed a significant senescence-like phenotype in the stroma. Moreover, PARPi-induced senescent CAFs displayed a senescence-associated secretory phenotype (SASP) profile that was sufficient to induce tumor resistance to PARPi in both homologous recombination-deficient (HRD) and proficient (HRP) ovarian cancer cells. Using the GLAD4U database, we found that bepotastine, an approved H1-antihistamine, inhibited the SASP of PARPi-primed CAFs at clinical serum concentrations. We further demonstrated that bepotastine attenuated fibroblast-facilitated tumor resistance to PARPi in 3D organotypic cultures and HRD-positive PDX models. Mechanistically, bepotastine suppressed PARPi-triggered SASP by inhibiting NF-κB signaling independent of the histamine H1 receptor. Taken together, our results highlight the importance of stromal TIS and SASP in PARPi resistance, and targeting SASP with bepotastine may be a promising therapeutic option for improving PARPi sensitivity in ovarian cancer.

Tumor‐associated macrophages (TAMs) play critical roles in reprogramming other immune cells and orchestrating antitumor immunity. However, the interplay between TAMs and tumor cells responsible for enhancing immune evasion remains insufficiently understood. Here, we revealed that interleukin (IL)‐1β was among the most abundant cytokines within the in vitro tumor‐macrophage coculture system, and enhanced IL‐1β expression was associated with impaired cytotoxicity of CD8+ T cells in human ovarian cancer, indicating the possibility that IL‐1β mediated immunosuppression during tumor‐TAMs crosstalk. Mechanistically, we demonstrated that IL‐1β significantly boosted programmed death‐ligand 1 (PD‐L1) expression in tumor cells via the activation of the nuclear factor‐κb signaling cascade. Specifically, IL‐1β released from TAMs was triggered by lactate, the anaerobic metabolite of tumor cells, in an inflammasome activation‐dependent manner. IL‐1β sustained and intensified immunosuppression by promoting C‐C motif chemokine ligand 2 secretion in tumor cells to fuel TAMs recruitment. Importantly, IL‐1β neutralizing antibody significantly curbed tumor growth and displayed synergistic antitumor efficacies with anti‐PD‐L1 antibody in tumor‐bearing mouse models. Together, this study presents an IL‐1β‐centered immunosuppressive loop between TAMs and tumor cells, highlighting IL‐1β as a candidate therapeutic target to reverse immunosuppression and potentiate immune checkpoint blockade.