Renal cell carcinoma (RCC) is a malignant tumour originating in the proximal tubules and accounts for approximately 90% of all kidney malignancies [
1]. Approximately two-thirds of patients present with metastatic disease at initial diagnosis or after surgery [
2]. Although the emergence of tyrosine kinase receptor inhibitors (TKIs), such as sunitinib and cabozantinib, has largely improved the prognosis of RCC patients, the inevitable development of resistance to these inhibitors has made it urgent to explore novel treatment strategies for RCC [
3,
4].
In recent years, immunotherapy has emerged as a promising therapeutic strategy and has been widely used in the treatment of various metastatic or advanced malignancies. As a first- or second-line treatment for RCC, immune checkpoint inhibitors (ICIs), alone or in combination with TKIs, provide a survival benefit and induce a robust, continuous, and specific immune response, but unfortunately have a low objective response rate (ORR) of 20–30% [
5,
6]. Therefore, improving the ORR of RCC patients to immunotherapy is vital at present. A precise understanding of the tumour immune microenvironment and the underlying mechanisms of the immune response in RCC is crucial in solving this problem.
Many randomized trials have tried to improve the ORR by combining immunotherapy with TKIs or radiotherapy, however, an increased incidence of side effects was often observed in patients who received combined therapies [
7]. Recently, hyperthermia has received increasing attention for its effectiveness in fighting tumours with minimal damage to normal tissues. Hyperthermia is thought to target tumours via multiple possible mechanisms. First, hyperthermia could damage tumour cells directly by inducing the denaturation of membrane proteins and DNA synthetase. For patients with pancreatic cancer, pancreaticoduodenectomy combined with intraperitoneal hyperthermic perfusion was demonstrated to be superior to pancreaticoduodenectomy alone in overall survival and 2-year survival rates [
8]. A phse III clinical trial verified that the median overall survival time of patients with ovarian cancer receiving postoperative hyperthermic intraperitoneal chemotherapy was 69.5 months which was longer than that in patients receiving normothermic intraperitoneal chemotherapy (61.3 months, p < 0.05) [
9]. Second, hyperthermia could reduce the physical barrier effect of tumours by alleviating their hardness and softening their extracellular matrix, thus contributing to improved drug penetration and immune cell infiltration [
10]. Third, hyperthermia could enhance the chemosensitivity and radiosensitivity of tumour cells. Recent evidence revealed that the 2- or 5-year recurrence/progression-free rate in patients with nonmuscle-invasive bladder cancer receiving intravesical hyperthermic chemotherapy was higher than that in patients receiving intravesical chemotherapy alone [
11]. In addition, hyperthermia could enhance the therapeutic effectiveness of gemcitabine, 5-fluorouracil, and cisplatin on PDAC cells by decreasing the half-maximal inhibitory concentration (IC50) [
12]. Finally, hyperthermia has shown promise in activating the antitumour immune response both directly and indirectly. Adkins, I et al. found that heat-treated tumour cells were more easily phagocytosed by dendritic cells (DCs) and stimulated CD4
+ and CD8
+ T-cell activation and proliferation [
13]. Wang Z, et al. found that hyperthermia could efficiently induce antitumor immunity activation and ultimately inhibit breast cancer growth by using tumor-bearing mice model [
14]. Additionally, in mouse melanoma, hyperthermia was found to promote the secretion of IL-6, IL-12 and CCL2 which contributed to the activation of the immune microenvironment [
15]. Furthermore, a promising role of hyperthermia plus ICIs strategy has gained more and more attention, and many ongoing clinical trials are discovering the synergistic effect between hyperthermia and ICIs [
16].
In the current study, we primarily investigated the effect of hyperthermia on RCC cellular function and cell apoptosis. Additionally, we characterized the influence of hyperthermia on the immunogenicity of RCC cells at the cellular and molecular levels simultaneously.