Yingjie Bian

Chimeric antigen receptor (CAR) T cell therapy has demonstrated remarkable clinical efficacy, but challenges remain in the therapeutic application for solid tumors, primarily due to poor infiltration capacity, suboptimal activity, and tumor antigen escape. Here, we found that the chemokine CCL3 plays a significant role in modulating intratumoral T cell cytotoxicity. However, CCL3 alone is insufficient to sustain durable CAR‐T cell‐mediated tumor killing, largely due to tumor‐induced T cell death. In contrast, the combination of CCL3 with interleukin‐7 (IL‐7), a cytokine known to enhance T cell survival, exerted a potent synergistic effect. This combination significantly improved CAR‐T cell infiltration and longevity in solid tumors, leading to robust anti‐tumor efficacy without significant side effects or systemic toxicity. Mechanistically, CCL3 plus IL‐7 promoted RUNX3 expression and facilitated the differentiation of CD69 ⁺ CD103 ⁺ tissue‐resident memory T (Trm) cells. Furthermore, treatment with CAR‐T cells co‐expressing CCL3 and IL‐7 (3P7‐CAR‐T) remodeled the immune landscape of solid tumors, marked by an increased infiltration of M1‐like macrophages and CD103 ⁺ migratory dendritic cells. These changes enhance antigen presentation, thereby promoting the priming of endogenous anti‐tumor T cell responses. Taken together, our results demonstrate that CCL3 synergizes with IL‐7 to augment CAR‐T cell memory and therapeutic effectiveness in solid tumors.

While iron homeostasis in cancer cells is well-established, its role in mediating crosstalk between tumors and CD8 ⁺ T cells within the tumor microenvironment (TME) remains largely elusive. In this study, we compare iron levels across primary tissues populated by CD8 ⁺ T cells. Contrary to the systemic iron deficiency commonly found in cancer patients, the TME exhibits marked iron enrichment compared to lymphatic fluid and peripheral blood, a phenomenon primarily attributed to tumor necrosis. However, this iron-overloaded TME is detrimental to CD8 ⁺ T cells, triggering their ferroptosis and dysfunction. Mechanistically, tumoral T cell receptor (TCR) hyperactivation and tumor-derived hepcidin cooperatively downregulate the iron exporter SLC40A1 in CD8 ⁺ T cells, leading to intracellular iron accumulation and ferroptosis. Both genetic restoration of SLC40A1 and iron chelation inhibit CD8 ⁺ T cell ferroptosis and restore their cytotoxic activity, thereby suppressing tumor growth. Finally, to enhance chimeric antigen receptor T (CAR-T) cell adaptability to the iron-overloaded TME, we engineer SLC40A1-overexpressing CAR-T cells. These engineered cells resist ferroptosis induced by the TME and elicit potent anti-tumor immunity.

Metastasis is the primary cause of cancer mortality, and cancer frequently metastasizes to the liver. It is not clear whether liver immune tolerance mechanisms contribute to cancer outcomes. We report that liver metastases diminish immunotherapy efficacy systemically in patients and preclinical models. Patients with liver metastases derive limited benefit from immunotherapy independent of other established biomarkers of response. In multiple mouse models, we show that liver metastases siphon activated CD8⁺ T cells from systemic circulation. Within the liver, activated antigen-specific Fas⁺CD8⁺ T cells undergo apoptosis following their interaction with FasL⁺CD11b⁺F4/80⁺ monocyte-derived macrophages. Consequently, liver metastases create a systemic immune desert in preclinical models. Similarly, patients with liver metastases have reduced peripheral T cell numbers and diminished tumoral T cell diversity and function. In preclinical models, liver-directed radiotherapy eliminates immunosuppressive hepatic macrophages, increases hepatic T cell survival and reduces hepatic siphoning of T cells. Thus, liver metastases co-opt host peripheral tolerance mechanisms to cause acquired immunotherapy resistance through CD8⁺ T cell deletion, and the combination of liver-directed radiotherapy and immunotherapy could promote systemic antitumor immunity.

Tumor-associated macrophages (TAMs) affect cancer progression and therapy. Ovarian carcinoma often metastasizes to the peritoneal cavity. Here, we found 2 peritoneal macrophage subsets in mice bearing ID8 ovarian cancer based on T cell immunoglobulin and mucin domain containing 4 (Tim-4) expression. Tim-4 ⁺ TAMs were embryonically originated and locally sustained while Tim-4 ^– TAMs were replenished from circulating monocytes. Tim-4 ⁺ TAMs, but not Tim-4 ^– TAMs, promoted tumor growth in vivo. Relative to Tim-4 ^– TAMs, Tim-4 ⁺ TAMs manifested high oxidative phosphorylation and adapted mitophagy to alleviate oxidative stress. High levels of arginase-1 in Tim-4 ⁺ TAMs contributed to potent mitophagy activities via weakened mTORC1 activation due to low arginine resultant from arginase-1–mediated metabolism. Furthermore, genetic deficiency of autophagy element FAK family-interacting protein of 200 kDa resulted in Tim-4 ⁺ TAM loss via ROS-mediated apoptosis and elevated T cell immunity and ID8 tumor inhibition in vivo. Moreover, human ovarian cancer–associated macrophages positive for complement receptor of the immunoglobulin superfamily (CRIg) were transcriptionally, metabolically, and functionally similar to murine Tim-4 ⁺ TAMs. Thus, targeting CRIg ⁺ (Tim-4 ⁺ ) TAMs may potentially treat patients with ovarian cancer with peritoneal metastasis.

Abnormal epigenetic patterns correlate with effector T cell malfunction in tumours^1,2,3,4, but the cause of this link is unknown. Here we show that tumour cells disrupt methionine metabolism in CD8⁺ T cells, thereby lowering intracellular levels of methionine and the methyl donor S-adenosylmethionine (SAM) and resulting in loss of dimethylation at lysine 79 of histone H3 (H3K79me2). Loss of H3K79me2 led to low expression of STAT5 and impaired T cell immunity. Mechanistically, tumour cells avidly consumed methionine and outcompeted T cells for methionine by expressing high levels of the methionine transporter SLC43A2. Genetic and biochemical inhibition of tumour SLC43A2 restored H3K79me2 in T cells, thereby boosting spontaneous and checkpoint-induced tumour immunity. Moreover, methionine supplementation improved the expression of H3K79me2 and STAT5 in T cells, and this was accompanied by increased T cell immunity in tumour-bearing mice and patients with colon cancer. Clinically, tumour SLC43A2 correlated negatively with T cell histone methylation and functional gene signatures. Our results identify a mechanistic connection between methionine metabolism, histone patterns, and T cell immunity in the tumour microenvironment. Thus, cancer methionine consumption is an immune evasion mechanism, and targeting cancer methionine signalling may provide an immunotherapeutic approach.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Chronic hepatitis B is caused by prolonged infection with the hepatitis B virus (HBV), which can substantially increase the risk of developing liver disease. Despite the development of preventive vaccines against HBV, a therapeutic vaccine inducing an effective antibody response still remains elusive. The preS1 domain of the large HBV surface protein is the major viral attachment site on hepatocytes and thus offers a therapeutic target; however, its poor immunogenicity limits clinical translation. Here, we design a ferritin nanoparticle vaccine that can deliver preS1 to specific myeloid cells, including SIGNR1⁺ dendritic cells (which activate T follicular helper cells) and lymphatic sinus-associated SIGNR1⁺ macrophages (which can activate B cells). This nanoparticle vaccine induces a high-level and persistent anti-preS1 response that results in efficient viral clearance and partial serological conversion in a chronic HBV mouse model, offering a promising translatable vaccination strategy for the functional cure of chronic hepatitis B.