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Background A major hurdle for effective engineered T cell therapies for solid tumors indications is the identification and targeting of a tumor-associated antigen that is expressed across heterogeneous tumor sub-types but not in healthy tissue. Disruption of the lipid bilayer asymmetry is a common feature observed in cancer cells that can contribute to immunosuppression in the cancer microenvironment. While normally sequestered to the inner leaflet in healthy cells, the TIM-4-Ligand, phosphatidylserine (PS), has been reported to be aberrantly upregulated on multiple cancer types. Effective T cell therapy is also hindered by loss of target antigen, t-cell exhaustion and poor durability—marked by limited proliferation, and loss of effector function. To address these challenges and target aberrantly exposed TIM-4-L, we generated a chimeric engulfment receptor consisting of a TIM-4 extracellular binding domain fused with the CD28, CD3zeta and a TLR2-TIR signaling domains, resulting in an exhaustion-resistant engineered T cell with both lytic and phagocytic functions to eliminate cancer cells.Methods CER-1236 was assessed for specificity against PS and other membrane phospholipids. CER-1236 was recursively stimulated with PS or CD3/CD28 poly-clonal stimulation; expansion, exhaustion markers, and cytokine profile were evaluated. Baseline PS was assessed on a range of hematological and solid tumor cell lines, and PS upregulation after exposure to T-cell conditioned media (CM) from differentially activated T cells and individual cytokines was assessed by flow cytometry.Results CER-1236 T cells selectively recognize and respond to TIM-4-L without cross-reactivity to other membrane phospholipids. TIM-4-L-specific activation of CER-1236 supported sustained expansion across multiple rounds of antigen stimulation and induced a robust, polyfunctional cytokine response encompassing effector, stimulatory, and chemotactic factors, in contrast with CD3/CD28 polyclonal stimulation, which induced exhaustion. Consistent with enhanced proliferation and function, CER-1236 had low expression of the exhaustion markers TIM-3, PD-1, and LAG-3. Notably, TIM-4-L exposure on tumor cells representing hematologic and solid tumor indications was increased by conditioned media from activated T cells, an effect mitigated by pan-caspase inhibition. Similar PS upregulation was observed following treatment with recombinant cytokines, suggesting a novel mechanism by which TIM-4-L can be induced on cancer cells.Conclusions Here, we demonstrate a novel engineered T cell targeting TIM-4-L, a cancer-associated antigen that can be upregulated by standard chemotherapeutics and inflammatory cytokines. CER-1236 demonstrated maintenance of proliferative and effector functions and low expression of canonical exhaustion markers after chronic stimulation, suggesting they are resistant to T-cell exhaustion.