Mitochondria and endoplasmic reticulum (ER) share structural and functional networks and activate well-orchestrated signaling processes to shape cells’ fate and function. While persistent ER stress (ERS) response leads to mitochondrial collapse, moderate ERS promotes mitochondrial function. Strategies to boost antitumor T-cell function by targeting ER–mitochondria cross-talk have not yet been exploited. Here, we used carbon monoxide (CO), a short-lived gaseous molecule, to test whether engaging moderate ERS conditions can improve mitochondrial and antitumor functions in T cells. In melanoma antigen-specific T cells, CO-induced transient activation of ERS sensor protein kinase R-like endoplasmic reticulum kinase (PERK) significantly increased antitumor T-cell function. Furthermore, CO-induced PERK activation temporarily halted protein translation and induced protective autophagy, including mitophagy. The use of LC3-GFP enabled differentiation between the cells that prepare themselves to undergo active autophagy (LC3-GFPpos) and those that fail to enter the process (LC3-GFPneg). LC3-GFPpos T cells showed strong antitumor potential, whereas LC3-GFPneg cells exhibited a T regulatory–like phenotype, harbored dysfunctional mitochondria, and accumulated abnormal metabolite content. These anomalous ratios of metabolites rendered the cells with a hypermethylated state and distinct epigenetic profile, limiting their antitumor activity. Overall, this study shows that ERS-activated autophagy pathways modify the mitochondrial function and epigenetically reprogram T cells toward a superior antitumor phenotype to achieve robust tumor control. Significance: Transient activation of ER stress with carbon monoxide drives mitochondrial biogenesis and protective autophagy that elicits superior antitumor T-cell function, revealing an approach to improving adoptive cell efficacy therapy.

Despite rapid advances in the field of immunotherapy, the elimination of established tumors has not been achieved. Many promising new treatments such as adoptive cell therapy (ACT) fall short, primarily due to the loss of T cell effector function or the failure of long-term T cell persistence. With the availability of new tools and advancements in technology, our understanding of metabolic processes has increased enormously in the last decade. Redundancy in metabolic pathways and overlapping targets that could address the plasticity and heterogenous phenotypes of various T cell subsets have illuminated the need for understanding immunometabolism in the context of multiple disease states, including cancer immunology. Herein, we discuss the developing field of T cell immunometabolism and its crucial relevance to improving immunotherapeutic approaches. This in-depth review details the metabolic pathways and preferences of the antitumor immune system and the state of various metabolism-targeting therapeutic approaches.

Patients with Alzheimer's disease (AD) have a decreased incidence of cancer, with a cross-sectional analysis of a nationwide sample of adults finding 21-fold higher odds of cancer diagnosis in non-AD individuals compared with those with AD. In this study, we demonstrated that mitochondrial localization of AD-associated amyloid-β precursor protein (APP) and its cleavage product amyloid-β 40, but not mutant APP that lacks a mitochondrial localization signal, inhibits lipid stress–mediated hyperactive mitophagy in aging T cells, improving their antitumor functions. Growth of melanoma xenograft or carcinogen-induced oral cancer models was highly reduced in AD mice. Additionally, adoptive cell transfer–based immunotherapy using aging T cells isolated from AD mice suppressed tumor growth. The metabolic signature of stress-dependent mitophagy in T cells showed fumarate depletion, which was linked to decreased succination of Parkin and enhanced mitochondrial damage. Mechanistically, APP interaction with the TOMM complex at the outer mitochondrial membrane attenuated trafficking of ceramide synthase CerS6 to mitochondria in aging AD T cells, preventing ceramide-dependent mitophagy. Thus, APP restored mitochondrial fumarate metabolism and Parkin succination, improving antitumor functions of AD T cells in vitro and in vivo. Exogenous fumarate supplementation or healthy AD mitochondria transfer functionally mimicked the AD/APP phenotype in aging T cells, enhancing their antitumor activity to control tumor growth. Moreover, T cells isolated from aging donors showed elevated mitophagy with fumarate depletion, which was restored in T cells isolated from age-matched patients with AD. Together, these findings show that AD protects T cells against ceramide-dependent mitophagy and fumarate depletion to enhance antitumor functions. Significance: The reduced cancer risk in Alzheimer's disease patients is mediated by the amyloid-β 40 peptide, which inhibits aging-dependent mitophagy in T cells to improve antitumor immunity. See related commentary by Bieberich, p. 3579

Secreted frizzled-related protein 2 (SFRP2) promotes the migration/invasion of metastatic osteosarcoma (OS) cells and tube formation by endothelial cells. However, its function on T-cells is unknown. We hypothesized that blocking SFRP2 with a humanized monoclonal antibody (hSFRP2 mAb) can restore immunity by reducing CD38 and PD-1 levels, ultimately overcoming resistance to PD-1 inhibitors. Treating two metastatic murine OS cell lines in vivo, RF420 and RF577, with hSFRP2 mAb alone led to a significant reduction in the number of lung metastases, compared to IgG1 control treatment. While PD-1 mAb alone had minimal effect, hSFRP2 mAb combination with PD-1 mAb had an additive antimetastatic effect. This effect was accompanied by lower SFRP2 levels in serum, lower CD38 levels in tumor-infiltrating lymphocytes and T-cells, and lower PD-1 levels in T-cells. In vitro data confirmed that SFRP2 promotes NFATc3, CD38 and PD-1 expression in T-cells, while hSFRP2 mAb treatment counteracts these effects and increases NAD⁺ levels. hSFRP2 mAb treatment further rescued the suppression of T-cell proliferation by tumor cells in a co-culture model. Finally, hSFRP2 mAb induced apoptosis in RF420 and RF577 OS cells but not in T-cells. Thus, hSFRP2 mAb therapy could potentially overcome PD-1 inhibitor resistance in metastatic osteosarcoma.

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

CD38 negatively impacts T-cell metabolic phenotypes