Several tumor entities have been reported to overexpress K_Ca3.1 potassium channels due to epigenetic, transcriptional, or post-translational modifications. By modulating membrane potential, cell volume, or Ca²⁺ signaling, K_Ca3.1 has been proposed to exert pivotal oncogenic functions in tumorigenesis, malignant progression, metastasis, and therapy resistance. Moreover, K_Ca3.1 is expressed by tumor-promoting stroma cells such as fibroblasts and the tumor vasculature suggesting a role of K_Ca3.1 in the adaptation of the tumor microenvironment. Combined, this features K_Ca3.1 as a candidate target for innovative anti-cancer therapy. However, immune cells also express K_Ca3.1 thereby contributing to T cell activation. Thus, any strategy targeting K_Ca3.1 in anti-cancer therapy may also modulate anti-tumor immune activity and/or immunosuppression. The present review article highlights the potential of K_Ca3.1 as an anti-tumor target providing an overview of the current knowledge on its function in tumor pathogenesis with emphasis on vasculo- and angiogenesis as well as anti-cancer immune responses.

K_Ca3.1 K⁺ channels reportedly contribute to the proliferation of breast tumor cells and may serve pro-tumor functions in the microenvironment. The putative interaction of K_Ca3.1 with major anti-cancer treatment strategies, which are based on cytotoxic drugs or radiotherapy, remains largely unexplored. We employed K_Ca3.1-proficient and -deficient breast cancer cells derived from breast cancer-prone MMTV-PyMT mice, pharmacological K_Ca3.1 inhibition, and a syngeneic orthotopic mouse model to study the relevance of functional K_Ca3.1 for therapy response. The K_Ca3.1 status of MMTV-PyMT cells did not determine tumor cell proliferation after treatment with different concentrations of docetaxel, doxorubicin, 5-fluorouracil, or cyclophosphamide. K_Ca3.1 activation by ionizing radiation (IR) in breast tumor cells in vitro, however, enhanced radioresistance, probably via an involvement of the channel in IR-stimulated Ca²⁺ signals and DNA repair pathways. Consistently, K_Ca3.1 knockout increased survival time of wildtype mice upon syngeneic orthotopic transplantation of MMTV-PyMT tumors followed by fractionated radiotherapy. Combined, our results imply that K_Ca3.1 confers resistance to radio- but not to chemotherapy in the MMTV-PyMT breast cancer model. Since K_Ca3.1 is druggable, K_Ca3.1 targeting concomitant to radiotherapy seems to be a promising strategy to radiosensitize breast tumors.