The male reproductive immune system plays a pivotal role in safeguarding sperm from immune attacks and preventing the incursion of foreign pathogens. Nucleotide-binding and oligomerization domain-like receptors (NOD-like receptors, NLRs) family protein domain containing 3 (NLRP3) is a cytoplasmic sensor binding to the inflammasome and critically involved in inducing innate immunity in the testes. It also has a substantial impact on male reproductive immunity, which is closely associated with male infertility stemming from disorders related to the male reproductive immune system. This review introduces the distinct characteristics of the NLR family, elucidates the activation pathways and factors of NLRP3 inflammasomes, and discusses how they participate in male reproductive immune diseases such as bacterial orchitis, autoimmune orchitis, varicocele, and epididymitis. In bacterial orchitis, elevated levels of NLRP3 inflammasomes exacerbate the testicular inflammatory injury and lead to decreased testosterone, thus contributing to male infertility. In autoimmune orchitis, the NLRP3 inflammasomes inhibit testosterone synthesis by decreasing the expression of cytochrome P450, thereby impacting male reproductive function. Therefore, targeting NLRP3 could offer novel immunological strategies for the clinical treatment of male infertility.

The gut–tumor–microbiota axis has recently recalibrated our understanding of host metabolic and immune rheostasis, emerging as a critical determinant in precision oncology. Although systemic chemotherapy remains the cornerstone of cancer treatment, its long-term clinical efficacy is routinely subverted by primary and acquired chemoresistance. This review systematically decrypts the intricate, bidirectional crosstalk between chemotherapeutic agents and the microbiome, elucidating how cytotoxic stressors drive dysbiosis and how chemo-tolerant pathobionts undergo adaptive evolution under treatment-induced selective pressure. Moving beyond descriptive correlations toward a mechanistic understanding, we dissect the underlying molecular mechanisms through which the microbiota modulates therapeutic outcomes, spanning microbial-mediated drug sequestration (the “drug sink” effect) and metabolic reprogramming, the hijacking of host pro-survival cascades (e.g., Notch1, PI3K/AKT, and epigenetic m6A modifications), and the orchestration of intratumoral immunosuppressive niches. Finally, we evaluate the clinical translation of predictive microbial signatures for patient stratification and outline the therapeutic horizon of rationally defined consortia and synthetic biology. By leveraging the synergy of single-cell multi-omics and spatiotemporal imaging technologies, we propose a transition toward a microbiota-centered framework in precision oncology to overcome conventional therapeutic failure.