Before sperm-oocyte interaction and occurrence of fertilization as the first step to developing an embryo, the male gamete should mature in the male reproductive tract (MRT) and so on; after confronting with physiologic or pathologic environment of MRT, it should get over the female reproductive tract (FRT) as a new challenge (Saeidi et al., 2014, Wigby et al., 2019).

In the male body, after the late stages of spermatogenesis, sperm leaves its immune privilege site in the testis and face the male immune system for the first time while passing through the epididymis, vasa deferent, and urethra to finally ejaculate (Saeidi et al., 2014). At the next step, spermatozoa, as a foreign cell in the FRT, has to transit through a complex path including the vagina, cervix, and uterine to meet the oocyte in the oviduct, and during its journey should deal with a wide range of biomolecules and cells to survive (Mahdavinezhad et al., 2021).

The immune system in both genders has adapted to defend against pathogens and sexual infections while tolerating sperm antigens, and its highly regulated function is necessary for fertility (Zandieh et al., 2015). Accordingly, a significant part of the successful delivery of sperm to the fertilization site in the female oviduct depends on the immune system (Tecle et al., 2019, Wigby et al., 2019).

As seminal plasma accompanies sperm in part of this passage, most studies focused on the role of seminal fluid in sperm survival against immune responses. However, it is indicated that the interaction between semen and the female immune system needs the presence of sperm to trigger the inflammatory reactions required for immune tolerance (Mousavi et al., 2021). Despite many findings resulting from co-culture studies and detection of many biomarkers essential for cross-talk between sperm and reproductive system, there are still several missing points about the exact mechanism that leads to sperm survival and successful function until early embryo development (Mohammadi et al., 2022, Ajdary et al., 2021). In the present review, we aimed to review molecular mechanisms that assist the sperm in protecting itself during its journey after successful spermatogenesis until eventually fertilizing an oocyte.