Inflammatory bowel disease (IBD) is a chronic immune-mediated condition of the gastrointestinal tract, characterized by dysregulated inflammatory responses throughout the gastrointestinal tract. It includes two major phenotypes, Crohn’s disease (CD) and ulcerative colitis (UC), which present with varying gastrointestinal and systemic symptoms. The pathophysiology of IBD is multifactorial including genetic predisposition, mucosal and epithelial dysfunction, environmental injury, and both innate and adaptive immune response abnormalities. Several predisposing genetic factors have been associated with IBD explaining the strong hereditary risk for both CD and UC. For example, Caspase Recruitment Domain 9 (CARD9) variant rs10781499 increases risk for IBD, while other variants are specific to either CD or UC. CD is related to loss-of-function mutations in the nucleotide oligomerization domain containing the protein 2 (NOD2) gene and Autophagy-Related 16-like 1 (ATG16L1) gene. UC risk is increased particularly in Chinese populations by the A-1661G polymorphism of the Cytotoxic T-lymphocyte antigen 4 (CTLA-4) gene. This abnormal CTLA-4 interferes with B- and T-cell responses causing predisposition to autoimmune conditions. Previous studies suggested that IBD results from breakdown of the adaptive immune system, primarily of T-cells. However, new evidence suggests that a primary breakdown of the innate immune system in both CD and UC increases susceptibility to invasion by viruses and bacteria, with a compensatory overactivation of the adaptive immune system as a result. When this viral and microbial invasion continues, further damage is incurred, resulting in a downward cycle of further cytokine activation and epithelial damage. Released biomarkers also affect the permeability of the epithelial membrane, including lactoferrin, nitric oxide (NO), myeloperoxidase (MPO) and its activation of hypochlorous acid, matrix metalloproteinases (MMPs), especially MMP-9, omentin-1, and others. Increased macrophage and dendritic cell dysfunction, increased neutrophil activity, increased numbers of innate lymphoid cells, increased T-cells with decreased regulatory T-cells (Tregs), and changes in B-cell populations and immunoglobulin (Ig) functions are all associated with IBD. Finally, treatment of IBD has typically consisted of medical management (e.g., aminosalicylates and corticosteroids) and lifestyle modification, and surgical intervention in extreme cases. New classes of medications with more favorable side effect profiles include anti-integrin antibodies, vedolizumab, etrolizumab, and carotegrast methyl. Additionally, fecal microbiota transplant (FMT) is a newer area of research for treatment of IBD along with TNF-blockers, JAK inhibitors, and S1PR modulators. However, expense and long preparation time have limited the usefulness of FMT.

The role of the unfolded protein response (UPR) in plasma cells (PC) and their malignant multiple myeloma (MM) counterparts is a well described area of research. The importance of autophagy in these cells, as well as the interplay between autophagy and the UPR system, has also been well studied. In this review, we will discuss the relationship between these two cellular responses and how they can be utilized in MM to account for the high levels of monoclonal immunoglobulin (Ig) protein synthesis that is characteristic of this disease. Interactions between MM cells and the bone marrow (BM) microenvironment and how MM cells utilize the UPR/autophagy pathway for their survival. These interacting pathways form the foundation for the mechanism of action for bortezomib, a proteasome inhibitor used to modify the progression of MM, and the eventual drug resistance that MM cells develop. One important resistance pathway implicated in MM progression is caspase 10 which attenuates autophagy to maintain its prosurvival function and avoid cell death. We lay a groundwork for future research including 3D in vitro models for better disease monitoring and personalized treatment. We also highlight pathways involved in MM cell survival and drug resistance that could be used as new targets for effective treatment.

B cell maturation antigen (BCMA)-targeted chimeric antigen receptor T cell (CAR-T) therapy has transformed the treatment landscape for relapsed or refractory multiple myeloma (MM), with products such as idecabtagene vicleucel and ciltacabtagene autoleucel achieving high initial response rates, and in selected patient populations, durable treatment-free remission. However, a substantial proportion of patients still experience relapse, including antigen-positive progression, highlighting persistent limitations in long-term disease control across diverse clinical settings. An increasing body of evidence indicates that resistance to CAR-T therapy in MM is driven not only by tumor-intrinsic factors, but also by extrinsic pressures imposed by the bone marrow microenvironment (BMME). This review integrates current understanding of tumor-niche interactions that impair CAR-T persistence, trafficking, and effector function, including immunosuppressive cellular networks, inhibitory cytokine signaling, metabolic constraints, stromal adhesion, antigen modulation, and marrow remodeling. This review further examines emerging therapeutic strategies and next-generation CAR-T platforms.