Antigen cross-presentation by dendritic cells (DCs) is essential for establishing adaptive immunity against intracellular pathogens and cancer through cytotoxic CD8+ T cell activation. DC-based vaccines for cancer immunotherapy hold great potential, yet clinical efficacy has remained low, leaving room for improvement. Our previous work showed the store-operated calcium entry (SOCE) regulator STIM1 was required for efficient cross-presentation, at least in part through regulation of phagosome maturation. To gain further insight into how SOCE impacts cross-presentation as well as to identify compounds of potential therapeutic interest, 13 commercial and custom SOCE-stimulating small-molecules were screened for their ability to enhance CD8+ T cell responses to ovalbumin (OVA)-derived antigen-loaded DCs using murine cell lines B3Z and JAWSII. Compound 1 (Cp1) and Cp2 were further tested and showed improved responses (proliferation, IL2 and/or IFNG secretion) using human monocyte-derived DC(MoDC):T cell co-cultures as well as primary bone-marrow-derived DCs (BMDC) both in vitro and in vivo. Cp1 and Cp2 both produced calcium signals with distinct kinetics that were reduced by Orai-channel blocker GSK-7579A and IP3R-inhibitor xestospongin C. Neither drug impacted surface expression of MHC-I-peptide complexes, MHC-II or CD86, nor migration of antigen-loaded DCs in vitro or in vivo, but Cp1 reduced antigen degradation. Bulk RNA sequencing on MoDCs revealed that Cp1 induced significant reprogramming of the transcriptomic profile, including changes to gene expression indicative of endoplasmic reticulum stress, migration and adaptive immune responses, but there was no measurable impact of Cp2 on global gene expression. However, cytokine array analysis of SOCE-treated BMDCs indicated changes to the secretion of soluble ICAM-1, CXCL11 and CXCL13 induced by both Cp1 and Cp2, which may contribute to their impact on DC activity. Importantly, in a murine model of anti-melanoma DC-vaccine immunotherapy, treatment of BMDCs with Cp1 and Cp2 during antigen loading induced a protective effect, reducing the tumor growth rate and increasing tumor infiltration and anti-tumor activity of not only CD8 T cells but also CD4 T, NK, CD80+ B cells and M1 macrophages. Altogether, these results demonstrate that SOCE modulators can efficiently enhance antigen cross-presentation in mice and human DCs and boost in vivo anti-tumor responses in mice, thereby being promising candidates to improve anti-cancer cell therapies.