The history of cryotherapy for prostate cancer Cryotherapy is the earliest minimally invasive ablation technique for tumors in human history and has a history of more than 100 years, and the application of cryotherapy to the treatment of prostate disease has a history of half a century. In 1966, the transurethral route was used to treat prostatic hyperplasia with satisfactory results. In 1968, Flocks was the first to treat prostate cancer with direct perineal incisional cryotherapy, and Kunit et al. used open cryosurgery to treat 101 cases of prostate cancer with a 5-year survival rate similar to that of radical surgery. Soon after, Bonney et al. reported 229 cases of prostate cancer treated with cryotherapy, and the local control of tumor and 10-year survival rates were similar to those of radical surgery and external radiation radiotherapy, which attracted attention in the field of related treatments. However, the development of this technology was limited and interrupted again due to technical reasons such as refrigerant, temperature control, real-time monitoring, and complications such as necrotic tissue loss and urinary fistula after cryotherapy. In 1988, Onik used transrectal ultrasound guidance and monitoring to freeze prostate cancer treatment by percutaneous puncture, providing a safer and more effective clinical method; subsequently, the urethral insulation device and cryo-thermometry probe protection technology further reduced the incidence of necrotic tissue shedding from the urethra after freezing and the side effects on adjacent tissues. In 1993, Endocare developed the argon-helium cryotherapy system, which made the precise control of temperature a reality and reduced the treatment complications while improving the tumor treatment effect. Prostate cancer cryotherapy uses argon-helium cryotherapy system, which is mainly composed of console, freezer and temperature probe, generally equipped with 4~8 cold and heat insulated superconducting freezers, the diameter of the freezers used for prostate cancer treatment is mainly 1.7~2 mm. After the release of the Joule-Thomason gas throttling effect, a rapid expansion is produced and the cryostat is rapidly cooled to about -140°C within 1~2 min. Under controlled output power, the 2 mm diameter cryostat can form a “pear” shaped ice ball in the tumor tissue, causing physical damage to the tumor cells and resulting in coagulative necrosis. Ar-He knife treatment of the prostate is guided by transrectal ultrasound, a cryoprobe is positioned percutaneously in the perineum and punctured into the prostate, the argon gas is activated, and the output power is adjusted between 100% and 5% for approximately 10 minutes, with ultrasound and temperature probes monitoring the freezing range throughout. Then proceed to helium warming for approximately 10-15 minutes, also using ultrasound and temperature probes to monitor ice ball dissolution after warming. One treatment cycle is completed and a total of 2 cycles are performed. During the procedure, the urethra is protected with warm water of about 37°C continuously circulated by an insulated urinary catheter. Schematic diagram of prostate cryotherapy 3. Effectiveness of prostate cancer cryotherapy A wealth of clinical data has been accumulated on prostate cancer cryotherapy. The American Urological Association released the Statement of Best Practices for Cryotherapy of Prostate Cancer (hereinafter referred to as the Statement) in December 2008. The Statement evaluates the efficacy, safety, and indications for the use of cryotherapy for prostate cancer as the treatment of choice or salvage therapy for patients with early-stage prostate cancer based on Level II2, II3, and III evidence, and confirms the efficacy of cryotherapy for prostate cancer. The Statement also developed treatment-related best clinical practice approaches that are important for clinical guidance and reference. In 2008, the International Cryotherapy Online Database (COLD) published the results of a large international set of 5-year follow-up studies of prostate cancer cryotherapy. The study analyzed 2,558 patients who received prostate cryotherapy, with a median age of 70 years, a median follow-up time of 1.5 years, and 419 patients with more than 5 years of follow-up. The 5-year biochemical progression-free survival rates of patients in the low-risk, intermediate-risk and high-risk groups were 89.2%, 83.7% and 80.2%, respectively. In 2008, Cohen et al. used cryotherapy to treat 370 patients with limited prostate cancer and retrospectively analyzed the results and found that the 10-year negative biopsy rate was 76.96%; the 10-year biochemical progression-free survival rates were 80.56%, 74.16% and 45.54% in the low-risk, intermediate-risk and high-risk groups, respectively; 2% of patients developed urinary incontinence, and Urethro-rectal fistula occurred in 0.5%. The long-term follow-up results of prostate cancer cryotherapy show that it is comparable to surgery and has a wide clinical application prospect. Prostate cancer cryotherapy is a minimally invasive treatment technique, which is characterized by mild side effects, few complications and safe treatment compared with surgery and radiotherapy, but complications are still a problem that cannot be ignored. Complications include: urinary incontinence, impotence, and secondary urinary tract obstruction. In addition, pelvic pain, swelling of the perineum, scrotum or penis, hematuria, urinary tract infection, paronychia and pubitis can also occur. In 2008, (Jones) et al. analyzed 1198 patients in the COLD database and found that the incidence of urinary incontinence and urethrorectal fistula was 4.8% and 0.4%, respectively. (Bahn) et al. analyzed data from 590 patients and found the incidence of urinary incontinence, urinary tract obstruction, and urethrorectal fistula to be 4.3%, 5.5%, and 0.1%, respectively. （More favorable results were reported by (Gary) and (Polascik), where the incidence of urinary incontinence was only 1 or 2 %. Erectile dysfunction is considered to be the most common complication associated with injury to the peripheral vasculature and nerve bundles and usually occurs within one month of treatment. With partial reconstruction of nerve function, some patients can achieve some degree of recovery of erectile capacity within 2 to 3 years. Some studies have shown that supplementing erectile function restoration drugs before and after treatment can partially solve the problem of erectile dysfunction. 5.Prostate Cancer Cryotherapy – Progress in Cryoimmune Research The recurrence or metastasis of prostate cancer is an important factor affecting the long-term outcome of patients, and is one of the major issues that need to be addressed in the relevant research fields at present. Cryoablation is the in situ destruction of tumor in vivo, and the necrotic tumor cells release a series of cytokines to induce cryoimmune response in the body, and the related mechanism is not yet understood. Therefore, the organic combination of local tumor cryoablation and systemic anti-tumor immunotherapy forms a new concept of cryoimmunotherapy, which provides new techniques and strategies for controlling tumor recurrence and metastasis and conducting comprehensive treatment. Currently, most scholars believe that tumor cells, after necrosis by cryoablation therapy, release tumor-associated antigens, which are presented by antigen-presenting cells (APCs) to helper T cells (Th), which activate and produce a series of cytokines to further activate cytotoxic T lymphocytes (CTLs) and exert specific killing effects on tumor cells.