Attenuated Salmonella as a PD-1/PD-L1 SiRNA delivery system for colorectal cancer, hepatocellular carcinoma, and melanoma: A systematic review.

[BACKGROUND] Melanoma, colorectal cancer (CRC), and hepatocellular cancer (HCC) overexpress the PD-1/PD-L1 pathway to evade the immune response. Immune Checkpoint Inhibitors (ICIs) suppress this mechanism but lack specificity, leading to immune-related adverse events (irAEs). Small-interfering RNA (siRNA) offers precise gene suppression but requires a protective delivery vector. Attenuated Salmonella, with tumor-targeting and immunomodulatory properties, is a promising carrier.

[METHODS] Five databases were systematically searched until August 14th, 2025. Relevant studies were assessed for quality of reporting and risk of bias using the ARRIVE and SYRCLE tools, respectively.

[RESULTS] Weighted quantitative analysis of eleven murine studies (>200 mice) demonstrates that siRNA-Salmonella therapy caused a significant suppression of PD-1/L1 expression and reduction of tumor weight in both CRC and HCC. In addition, marked cleaved-caspase-3 expression and CD8⁺ cell infiltration into tumor tissue were seen across all tumor types. Notably, comparison reveals that the strongest antitumor effects were observed in HCC and melanoma. CRC showed more modest effects, mirroring clinical ICI responses, which may be attributed to the low immunogenicity of the microsatellite-stable models used.

[CONCLUSION] SiRNA-PD-1/PD-L1 demonstrates excellent antitumor effects in HCC and melanoma, and to a lesser extent, CRC. Salmonella, with tumor-targeting and immunomodulatory capabilities, presents itself as a near-ideal carrier for anticancer siRNA. Despite various siRNA therapeutics already being available, and several clinical trials of anticancer siRNA still in their initial stages, no trial to date has combined PD-1/PD-L1 as a target with Salmonella as a carrier. The promising results of this combination warrant more extensive in vivo investigations to support its advancement into clinical trials.