Immune cells-enhanced immunotherapy exhibits unprecedented overall survival-prolongation even curable in some cancer patients. Although so, most of the patients show no response. Tumor microenvironment (TME) where immune cells settle down has multi-faceted influences, but usually creates an immunosuppressive niche that facilitating tumor cells escape from immune attack. The metabolites and malnutrition of TME exert enormous effects on the resident immune cells, but the underlying mechanism is largely unknown. The stromal interaction molecules 2 (STIM2) is an endoplasmic reticulum (ER) calcium (Ca2+) sensor to maintain Ca2+ homeostasis. Notably, the cytosol STIM2 C-terminus is long with various domains that are available for the combination or/and molecular modification. This distinct structure endows STIM2 with a high susceptibility to numerous permeable physico-chemical molecules or protein interactions. STIM2 and its variants are extensively expressed in various immune cells, especially in T immune cells. STIM2 was reported closely correlated with the function of immune cells via regulating Ca2+ signaling, energy metabolism and cell fitness. Herein, we sum the latest findings on the STIM2 structure, focusing on its distinct characteristics and profound effect on the regulation of Ca2+ homeostasis and multi-talented functionality. We also outline the advancements on the underlying mechanism how STIM2 anomalies influence the function of immune cells and on the turbulent expression or/and amenably modification of STIM2 within the tumor niches. Then we discuss the translation of these researches into antitumor approaches, emphasizing the potential of STIM2 as a therapeutic target for direct inhibition of tumor cells or more activation towards immune cells driving to flare TME. This review is an update on STIM2, aiming to rationalize the potential of STIM2 as a therapeutic target for immunomodulation, engaging immune cells to exert the utmost anti-tumor effect.
