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Background Bispecific antibodies (BsAbs) targeting PD-1 and VEGF and bispecific T cell engagers (BiTEs) have the potential to transform cancer treatment, however only a subset of patients obtain deep and durable responses. BiTEs show potent anti-tumor activity by redirecting T cells to tumor cells expressing the targeted antigen while PD-1/VEGF BsAbs aim to address TME-related resistance by combining immune checkpoint blockade with angiogenesis inhibition to enhance T cell function. Despite these advancements, combining these immunotherapies with complementary strategies is critical to unlock their full potential.Interleukin-2 (IL-2) promotes the proliferation and effector function of T cells. High-dose IL-2 monotherapy can induce complete responses in cancer patients, but its clinical application is severely limited by acute vascular toxicities, notably capillary leak syndrome and severe hypotension via the systemic activation of lymphocytes and natural killer (NK) cells. IL-2 activates lymphocytes and NK cells through the intermediate-affinity dimeric IL-2 receptor (IL-2Rβγ, composed of CD122/CD132). In contrast, certain lymphocytes such as antigen-activated T-cells exhibit increased sensitivity to IL-2 due to their expression of the high-affinity trimeric IL-2 receptor (IL-2Rαβγ, composed of CD25/CD122/CD132). To avoid systemic lymphocyte and NK cell activation, but maintain anti-tumor efficacy, we have developed a novel pegylated, α/β-IL-2 agonist (STK-012) engineered for preferential binding to the IL-2Rabg receptor, which is highly upregulated on antigen-activated T-cells.Methods and Results We show that the murine surrogate of STK-012, mSTK-012, is effective in various syngeneic solid tumor models without inducing acute vascular toxicities. mSTK-012 led to enhanced expansion of tumor antigen-specific CD25 +PD-1+CD8+ T cells both systemically and within the tumor microenvironment, resulting in complete responses and durable tumor immune memory with mSTK-012 monotherapy.Furthermore, mouse tumor models resistant to PD1/VEGF BsAbs or different targeting BiTEs were developed. We demonstrate that mSTK-012, in combination with either of these modalities, further enhanced intratumoral T cell proliferation, infiltration, and activity, leading to enhanced thereby rescuing anti-tumor efficacy. Also, combination treatment of mSTK-012 with either PD1/VEGF BsAbs or BiTEs did not result in acute vascular toxicities.Conclusions Currently, STK-012 is in Phase I trials for first line Non-small cell lung cancer (NSCLC) patients ( NCT05098132) in combination with pembrolizumab and chemotherapy. These findings highlight the potential of STK-012 to overcome key limitations of the next wave immunotherapies by selectively expanding and activating antigen-specific T cells while avoiding typical IL-2 systemic toxicities.