STIM1 (Stromal Interaction Molecule 1)

Golgi dispersal is associated with increased organelle volume and surface area to accommodate heightened trafficking and processing. These findings position STIM1 and ORP5 as biomarkers of aggressive PCa and show that high-Man enrichment is not due to defective maturation but reflects a glycan pool that cancer cells actively utilize, suggesting that the concept of ER stress response in PCa should be redefined to include Golgi reorganization and altered ER-PM junctions.

Collectively, these results demonstrate that SOCE-mediated calcium signaling and downstream kinases regulate IFN-γ-induced PD-L1 expression and suggest that targeting SOCE components could represent a novel therapeutic approach to overcoming tumor immune evasion in OSCC. (132 words).

Furthermore, principal PCA/FEL analyses have validated their conformational stability within a membrane environment. These findings provide novel insights into the structural gating processes of hORAI1 and emphasize the therapeutic potential of small compounds that target its closed state to inhibit calcium-mediated carcinogenesis in TNBC.

Loss of these components amplifies PERK signaling and selectively kills cancer cells while sparing normal cells. These findings uncover a cancer-specific role of VDACs in ERAD regulation and calcium signaling, highlighting a therapeutically actionable vulnerability.

Our findings identify a distinctive calcium- and stemness-based signature in BMresLC, representing a pre-MRD survival state characterized by slow cycling rather than enrichment in strict quiescence. This pre-therapeutic signature may contribute to MRD establishment and relapse risk in AML.

Unexpectedly, acid-ASIC3 signaling inhibits both murine and human LIC activities in a noncanonical manner by interacting with the N-terminal of STIM1 to reduce calcium-mediated CAMK1-CREB-MEIS1-LDHA levels, without inducing cation currents. This study reveals a pathway in suppression of leukemogenesis in the acidic BM niche and provides insight into targeting LICs or other cancer stem cells through pH-dependent ASICs.

The evidence, similar to the cellular experiments in vitro, was also observed in animal experiments in vivo. Our research results provide a new mechanism for the role of calcium homeostasis imbalance in arsenic-induced initiation and progression of bladder cancer.

Store-operated calcium entry-based proteins have been proposed as therapeutic cancer targets because inhibition of these proteins disrupts Ca2+ influx, thereby decreasing cell proliferation in certain cancers. Additionally, store-operated calcium entry-based proteins are implicated in many other disease states such as Stormorken syndrome, tubular aggregate myopathy, and immunodeficiency, highlighting the therapeutic relevance of these proteins.

Previously, we showed that 1,2,3,4-dithiadiazole derivatives are negative modulators of store-operated calcium channels that are normally activated by STIM1 and STIM2 proteins. Here, we studied the specificity of action of one of the most effective compounds of this class, 3-(4-nitrophenyl)-5-phenyl-3H-1,2,3,4-dithiadiazole-2-oxide, on STIM1- and STIM2-mediated store-operated calcium entry and concluded that it blocks calcium entry through store-operated channels activated by both STIM1 and STIM2.

Notably, combining light-activated engineered macrophages with temozolomide in melanoma models resulted in synergistic inhibition of tumor growth. This synergy is accompanied by a profound remodeling of the tumor immune microenvironment, characterized by M1-driven reversal of chemoresistance and enhanced infiltration of cytotoxic CD8+ T cells. Our findings establish a proof-of-concept for optogenetic regulation of macrophage polarization and demonstrate its feasibility for enhancing antitumor effects and chemosensitivity in melanoma models, providing a promising and controllable platform for macrophage-based immunotherapy.

In this issue, Militsin et al. (https://doi.org/10.1083/jcb.202411203) reveal how STIM1 and STIM2-beyond their typical role as ER Ca2+ sensors that activate Orai1-control IP3R-mediated Ca2+ dynamics, thereby regulating breast cancer cell migration and invasion.

Although preclinical studies have demonstrated that calcium release-activated calcium (CRAC) channel inhibitors suppress tumour growth, challenges such as calcium signalling complexity and tissue-specific toxicity persist. Future research should integrate emerging technologies and systematic approaches to clarify the mechanisms underlying the dynamic regulation of calcium signalling networks, which will ultimately accelerate their clinical translation and therapeutic application.