The role of tumor microenvironment (TME)–associated inadequate protein modification and trafficking due to insufficiency in Golgi function, leading to Golgi stress, in the regulation of T cell function is largely unknown. Here, we show that disruption of Golgi architecture under TME stress, identified by the decreased expression of GM130, was reverted upon treatment with hydrogen sulfide (H ₂ S) donor GYY4137 or overexpressing cystathionine β-synthase (CBS), an enzyme involved in the biosynthesis of endogenous H ₂ S, which also promoted stemness, antioxidant capacity, and increased protein translation, mediated in part by endoplasmic reticulum–Golgi shuttling of Peroxiredoxin-4. In in vivo models of melanoma and lymphoma, antitumor T cells conditioned ex vivo with exogenous H ₂ S or overexpressing CBS demonstrated superior tumor control upon adoptive transfer. Further, T cells with high Golgi content exhibited unique metabolic and glycation signatures with enhanced antitumor capacity. These data suggest that strategies to mitigate Golgi network stress or using Golgi ^hi tumor-reactive T cells can improve tumor control upon adoptive transfer.

Tissue-resident memory T cells (Trm) represent a diverse cell type with tissue-specific gene signatures that can operate as both effector and memory T cells. Trm cells play a crucial role in immune defense against infections and cancer. Recently, Trm cells have become appreciated as a critical responder to checkpoint immunotherapy and as a biomarker of favorable outcomes in cancer. Hence, it is of great clinical and therapeutic importance to investigate how Trm cells can be manipulated transcriptionally, epigenetically, or metabolically to improve their longevity and function. In this issue of Cancer Research, Feng and colleagues demonstrate that the transcription factor SCML4 is essential for the development and polyfunctionality of Trm cells. Fatty acids mediated the upregulation of SCML4 via the mTOR–IRF4–PRDM1 signaling pathway, which significantly enhanced tumor control in multiple aggressive murine tumor models and was associated with a favorable prognosis for patients with cancer. The findings also suggest that SCML4-mediated engagement of the HBO1–BRPF2–ING4 complex epigenetically reprogramed Trm cells by increasing the expression of several survival- and effector-associated molecules while blocking the expression of checkpoint inhibitors. Overall, Feng and colleagues highlight a critical activation target for tumor immunotherapy and provide a molecular perspective on recruiting antitumor Trm cells to the tumor niche by regulating fatty acids.See related article by Feng et al., p. 3368

Sphingosine 1-phosphate (S1P) is a potent bioactive sphingolipid that plays essential roles in regulating various immune responses, including lymphocyte trafficking, immune cell differentiation, and immunosurveillance. Different immune responses to S1P arise from the diverse Sphingosine 1-phosphate receptors (S1PRs) expressed on the cell surface, shaping unique, context-dependent responses to S1P. Beyond surface receptor engagement, intracellular S1P signaling is also being recognized as a crucial modulator of immune cell responses. Furthermore, the multifaceted S1P signaling axis has emerged as a key regulator of immune responses within the tumor microenvironment (TME), influencing both innate and adaptive immune cell behavior to facilitate tumor progression. A deeper mechanistic understanding of S1P signaling and its impact on immune cell fate is essential for developing novel therapeutic strategies to enhance anti-tumor responses. This review summarizes our current knowledge of how S1P influences immune cell function, with a specific focus on S1PR-dependent and S1PR-independent cellular signaling pathways. We also examine the alterations in immune cell responses that occur within the TME and current therapeutic strategies targeting S1P signaling.