Currently, the treatment options for gastrointestinal malignancies mainly include surgery, chemotherapy, radiotherapy, and molecular targeted therapy, etc. Drug therapy is one of the main treatments for patients with advanced stages, but the efficacy of chemotherapy seems to have reached a plateau, and the progress of traditional molecular targeted therapy is relatively slow. In addition, the benefits of the current chemotherapy combined with targeted therapy for patients with advanced stages of gastrointestinal malignancies are still not satisfactory. Tumor immunotherapy is an emerging therapeutic approach and is a current research hotspot, and there are hopes that immunotherapy can help further improve the prognosis and quality of life for patients with gastrointestinal malignancies. At the same time, potential targets of immunotherapeutic drugs and prognostic biomarkers for gastrointestinal malignancies have been less studied than other common cancers, such as lung cancer. Prognostic biomarker studies are the beginning of exploring new drug targets and revealing potential mechanisms of tumor progression. Immunotherapies, particularly PD1 or PD-L1 antagonists, have demonstrated effective therapeutic efficacy against various types of cancer. To date, many PD1 drugs are available for cancer treatment, and more than 100 PD1 drugs are in clinical trials. However, the question of how to screen sensitive patients and predict the efficacy of immunotherapy remains unresolved. In addition, predictive biomarkers and treatment guidelines for immunotherapy of gastrointestinal malignancies have hardly been studied.

Gastrointestinal (GI) cancers, including gastric cancer, colon cancer, liver cancer, esophageal cancer, and pancreatic cancer, seriously threaten the health of human beings worldwide with a high rate of morbidity and mortality. The clinical successes achieved with immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 and CTLA-4 have opened a new cancer therapy era and brought new hope to cancer patients. However, the overall response rate (ORR) of ICI monotherapy in the non-selective population is only about 20%, in which some patients subsequently develop immunotherapy resistance. Moreover, the remaining 70-80% of patients displayed primary resistance to ICIs, and a few patients even experienced hyper progression disease (HPD). Although PD-L1 expression, mismatch repair deficient (MMRd), high tumor mutational burden (TMB-H) , high homologous recombination deficiency (HRD), and tumor infiltrated immune cells (TILs) are known as effective biomarkers for immunotherapy, growing studies have reported that ICIs could not improve the OS of all patients with PD-L1 expression higher than 50%, and the ORR of MSI-H patients was only about 60%, whereas some patients with low PD-L1 expression or MSS could still benefit from immunotherapy, indicating the complexity of ICI resistance. Therefore, it is of great importance and significance to explore the prediction biomarkers for primary or acquired immunotherapy resistance and elucidate their underlying molecular mechanisms and develop reversal strategies. Due to the multiple steps of the cancer immune cycle and complex immune microenvironment, any disorders of immune cell infiltration or T cell activation, such as lack of antigens and/or their presentation, lack of response to antigen presentation, and T cell priming, could contribute to ICI resistance. The combination with anti-angiogenesis therapy, radiotherapy, chemotherapy, and other ICIs has improved the efficacy of ICI therapy to some extent in the clinic. Although numerous studies related to ICI resistance were reported in GI cancers, due to the strong spatial/temporal heterogeneity and the complex immune microenvironment in different kinds of GI cancers and different individuals, many questions about ICI resistance and reversal strategies remain unsolved. The aim of this Research Topic is to provide a forum to exhibit the latest research achievement related to the exploration of biomarkers for immunotherapy resistance including HPD and the underlying molecular mechanisms, as well as the development of reversal strategies in GI cancers. We hope this Research Topic will lead to a better understanding of precision cancer immunotherapy and provide useful clues for clinical application to benefit more GI cancer patients with immunotherapy.

Principles of Immunotherapy in Breast and Gastrointestinal Cancers: Activity, Mechanisms of Resistance and New Sensitization Strategies presents updated research findings on immunotherapy, with special focus on the mechanisms of resistance of those cancer types and how to overcome them. The book discusses topics such as tumor cell-intrinsic and extrinsic mechanisms of cancer resistance to immunotherapy; the role of currently available biomarkers; strategies to overcome therapeutic resistance; sensitizing agents for cancer resistance to cell mediated immunotherapy; and Immunotherapeutic approaches, mechanisms of resistance and sensitizing strategies in gastroesophageal and biliopancreatic tumors and colorectal cancer. It is a valuable resource for researchers, students and members of the biomedical and medical fields who want to learn more about resistance to immunotherapy and how to overcome it. - Presents relevant findings on immunotherapy for breast and GI cancer types in a synthetic and didactic way for easy consult - Describes resistance mechanisms of those cancer types and how to overcome them to improve immunotherapy outcomes - Encompasses several diagrams and figures to help readers get a clearer picture of the research findings and how they can be applied to the clinical setting

Gastrointestinal (GI) malignancies account for a large portion of cancers worldwide. Although incidence of esophageal, gastric, and colorectal cancers has decreased in recent years, pancreatic and liver cancer have increased. The mainstay of GI cancer therapy is chemoradiation and surgery. Despite significant medical advancements, diagnosis and therapy for GI cancers remain challenging due to tumor cell resistance to chemoradiotherapy. The tumor’s increased cell signalling due to excessive transcription factor activation and increased stellate cell activity leads to collagen deposition formation of a dense stroma around the tumor, which prevents drugs from reaching the malignant cells. This leads to tumor chemoresistance. To circumvent these difficulties, drug therapy targeting the tumor’s specific microenvironment and the additive anticancer effect of phytochemicals can allow for more effective treatment. This volume will be the first on the market on the topic of phytochemicals and their effect on the tumor microenvironment (TME). TME is an emerging area of research and the book will be a welcome introductory addition to the field.

Cancer immunotherapy, including immune checkpoint inhibitors (ICIs) and chimeric antigen receptor T-cell (CAR-T) therapy, has revolutionized the paradigm in cancer treatment. However, the clinical outcome of immunotherapy varies considerably among patients and only a minority of patients achieve long-term clinical benefits. This is largely attributed to the fact that existing cancer immunotherapies, which concentrate on several classical targets (CTAL-4, PD-1/PD-L1, etc.) and limited types of immune cell populations (T cells), are insufficient to cope with the complexity of highly heterogeneous tumor microenvironment (TME). This calls for more efforts to not only expand our toolbox for manipulating anticancer immunity but also diversify our combinational strategies. To this end, it is urgent to deeper our understanding of cancer immunotherapy by using both experimental and computational methodologies from multi-scale perspectives: 1) novel targets from either tumor cells or non-tumor cells within TME (e.g., tumor intrinsic resistance drivers, new immune checkpoints, neoantigens), 2) in-depth characterization of more immune cell populations (e.g., macrophages, Tregs, B cells) and their interactions and dynamics within TME, 3) landscape of actionable targets in patient populations for combination design. These efforts will open the avenue of rational design of combinational immunotherapies, allowing researchers and clinicians to design novel targeting therapeutics or to optimally orchestrate combinatory strategies aiming to surmount resistance mechanisms and improve clinical outcomes.