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Tumor microenvironment modulators have produced durable effects in cancer treatment. Targeting immune checkpoint receptors, such as PD-L1, has demonstrated efficacy in eliciting antitumor responses. However, resistance to immune checkpoint blockers (ICBs) has constrained the efficacy of these therapies. Previous studies showed a link between the expression of AXL receptor tyrosine kinase and resistance to ICBs. Therefore, designing combination treatments with synergistic mechanisms to overcome ICB-based resistance is needed. In addition to antibody-based therapies, gene silencing with siRNAs has recently been explored to alter the cancer environment to enhance the immune response. In this study, we targeted PD-L1 using an siRNA and AXL using a blocker (R428) in OVACAR-3 and CaSki cells, ovarian and cervical cancer cell lines, respectively, in the following groups: Scramble-siRNA, PD-L1-siRNA, Scramble-siRNA in conjunction with R428, PD-L1-siRNA in conjunction with R428, R428 monotherapy and untreated controls. Cell viability was assessed by MTT assay after 48 hours of treatment, and cisplatin sensitization was evaluated in resistant OVACAR-3 cells. Gene expression was analyzed by qRT-PCR, while flow cytometry quantified CD44+PD-L1+ populations, apoptosis (Annexin V/PI), and cell cycle distribution. The results showed a significant decrease in cell proliferation, suppression of EMT-regulating genes, reduction of stemness in cancer cells, increased apoptosis and disruption of the cell cycle in the studied cell lines. These findings suggest that simultaneous blockade of PD-L1 and AXL could serve as a novel tumor-suppressive strategy, especially for cancer patients resistant to ICBs.