STING licensing of type I dendritic cells potentiates antitumor immunity.

Stimulator of interferon genes (STING) is an immune adaptor protein that senses cyclic GMP-AMP in response to self or microbial cytosolic DNA as a danger signal. STING is ubiquitously expressed in diverse cell populations, including cancer cells, with distinct cellular functions, such as activation of type I interferons, autophagy induction, or triggering apoptosis. It is not well understood whether and which subsets of immune cells, stromal cells, or cancer cells are particularly important for STING-mediated antitumor immunity. Here, using a polymeric STING-activating nanoparticle (PolySTING) with a shock-and-lock dual activation mechanism, we show that conventional type 1 dendritic cells (cDC1s) are essential for STING-mediated rejection of multiple established and metastatic murine tumors. STING status in the host but not in the cancer cells (Tmem173-/-) is important for antitumor efficacy. Specific depletion of cDC1 (Batf3-/-) or STING deficiency in cDC1 (XCR1creSTINGfl/fl) abolished PolySTING efficacy, whereas depletion of other myeloid cells had little effect. Adoptive transfer of wild-type cDC1 in Batf3-/- mice restored antitumor efficacy, whereas transfer of cDC1 with STING or IRF3 deficiency failed to rescue. PolySTING induced a specific chemokine signature in wild-type but not Batf3-/- mice. Multiplexed immunohistochemistry analysis of STING-activating cDC1s in resected tumors correlates with patient survival. Furthermore, STING-cDC1 signature was increased after neoadjuvant pembrolizumab therapy in patients with non-small cell lung cancer. Therefore, we have defined that a subset of myeloid cells is essential for STING-mediated antitumor immunity with associated biomarkers for prognosis.

STING Licensing of Type I Dendritic Cells Potentiates Antitumor Immunity.

Stimulator of interferon genes (STING) is an immune adaptor protein that senses cyclic GMP-AMP (cGAMP) in response to self or microbial cytosolic DNA as a danger signal. STING is ubiquitously expressed in diverse cell populations including cancer cells with distinct cellular functions such as activation of type I interferons, autophagy induction, or triggering apoptosis. It is not well understood whether and which subsets of immune cells, stromal cells, or cancer cells are particularly important for STING-mediated antitumor immunity. Here using a polymeric STING-activating nanoparticle (PolySTING) with a "shock-and-lock" dual activation mechanism, we show type 1 conventional dendritic cell (cDC1) is essential for STING-mediated rejection of multiple established and metastatic murine tumors. STING status in the host but not in the cancer cells ( Tmem173 -/- ) is important for antitumor efficacy. Specific depletion of cDC1 ( Batf3 -/- ) or STING deficiency in cDC1 ( XCR1 cre STING fl/fl ) abolished PolySTING efficacy, whereas depletion of other myeloid cells had little effect. Adoptive transfer of wildtype cDC1 in Batf3 -/- mice restored antitumor efficacy while transfer of cDC1 with STING or IRF3 deficiency failed to rescue. PolySTING induced a specific chemokine signature in wildtype but not Batf3 -/- mice. Multiplexed immunohistochemistry analysis of STING-activating cDC1s in resected tumors correlates with patient survival while also showing increased expressions after neoadjuvant pembrolizumab therapy in non-small cell lung cancer patients. Therefore, we have defined that a subset of myeloid cells is essential for STING-mediated antitumor immunity with associated biomarkers for prognosis. One Sentence Summary: A "shock-and-lock" nanoparticle agonist induces direct STING signaling in type 1 conventional dendritic cells to drive antitumor immunity with defined biomarkers.

Membrane fusogenic nanoparticle-based HLA-peptide-addressing universal T cell receptor-engineered T (HAUL TCR-T) cell therapy in solid tumor.

T cell receptor-engineered T (TCR-T) cell therapy has demonstrated therapeutic effects in basic research and clinical trials for treating solid tumors. Due to the peptide-dependent recognition and the human leukocyte antigen (HLA)-restriction, TCR-T cell therapy is generally custom designed to target individual antigens. The lack of suitable universal targets for tumor cells significantly limits its clinical applications. Establishing a universal TCR-T treatment strategy is of great significance. This study designed and evaluated the HLA-peptide-addressing universal (HAUL) TCR-T cell therapy based on HLA-peptide (pHLA) loaded membrance fusogenic deliver system. The pHLA-NP-based tumor cell membrane modification technology can transfer the pHLA onto the surface of tumor cells through membrane fusogenic nanoparticles. Then tumor cells are recognized and killed by TCR-T cells specifically. The HAUL TCR-T cell therapy technology is a universal technology that enables tumor cells to be identified and killed by specific TCR-T cells, regardless of the HLA typing of tumor cells.

Enhanced systemic tumor suppression by in situ vaccine combining radiation and OX40 agonist with CpG therapy.

BACKGROUND: In situ tumor vaccine has been gradually becoming a hot research field for its advantage of achieving personalized tumor therapy without prior antigen identification. Various in situ tumor vaccine regimens have been reported to exert considerable antitumor efficacy in preclinical and clinical studies. However, the design of in situ tumor vaccines still needs further optimization and the underlying immune mechanism also waits for deeper investigation. METHODS: A novel triple in situ vaccine strategy that combining local radiation with intratumoral injection of TLR9 agonist CpG and OX40 agonist was established in this sturdy. Local and abscopal antitumor efficacy as well as survival benefit were evaluated in the bilateral tumors and pulmonary metastasis model of B16F10 melanoma. In situ vaccine-induced immune responses and immune-associated variation in tumor environment were further investigated using multiparameter flow cytometry and RNA sequencing. Base on the analysis, the RT + CpG + αOX40 triple in situ vaccine was combined with checkpoint blockade therapy to explore the potential synergistic antitumor efficacy. RESULTS: Enhanced tumor suppression was observed with minimal toxicity in both treated and untreated abscopal tumors after receiving RT + CpG + αOX40 triple vaccine. The introduction of local radiation and OX40 agonist benefit more to the inhibition of local and abscopal lesions respectively, which might be partially attributed to the increase of effector memory T cells in the tumor microenvironment. Further analysis implied that the triple in situ vaccine did not only activate the microenvironment of treated tumors, with the upregulation of multiple immune-associated pathways, but also enhanced systemic antitumor responses, thus achieved superior systemic tumor control and survival benefit. Moreover, the triple in situ vaccine synergized with checkpoint blockade therapy, and significantly improved the therapeutic effect of anti-programmed cell death protein (PD)-1 antibody. CONCLUSION: This triple combining in situ vaccine induced intensive antitumor responses, mediated effective systemic tumor control and survival benefit, and displayed impressive synergistic antitumor effect with checkpoint blockade therapy. These data preliminary confirmed the efficacy, feasibility and safety of the triple combining in situ vaccine, suggesting its great application potential as both monotherapy and a part of combined immunotherapeutic regimens in clinical scenario.

Implication of 99mTc-sum IL-2 SPECT/CT in immunotherapy by imaging of tumor-infiltrating T cells.

BACKGROUND: Although immune checkpoint blockade (ICB) and adoptive T cell transfer (ACT) therapy have achieved impressive clinical outcomes, majority of patients do not respond to immunotherapy. Tumor-infiltrating T cells, a critical factor to immunotherapy, is dynamically changing. Therefore, a reliable real-time in vivo imaging system for tumor-infiltrating T cells, but not immunohistochemical analyses, will be more valuable to predict response and guide immunotherapy. In this study, we developed a new SPECT/CT imaging probe 99mTc-sum IL-2 targeting the IL-2Rß/IL-2Rγ (CD122/CD132) receptor on tumor-infiltrating T cells, and evaluated its application in predicting the immune response to anti-PD-L1 (αPD-L1) therapy as well as tracking infused T cells in ACT therapy. METHODS: The binding affinity of the super mutated IL-2 (sum IL-2) in various T cell subtypes was measured. Sum IL-2 was subsequently labeled with 99mTc through Sortase-A mediated site-specific transpeptidation. SPECT/CT imaging and biodistribution studies of 99mTc-sum IL-2 were performed in a MC38 mouse model. Wild type IL-2 (IL-2) was used as control in the above studies. Finally, we evaluated 99mTc-sum IL-2 SPECT/CT for the detection of tumor-infiltrating T cells in the context of αPD-L1 immunotherapy and ACT therapy. RESULTS: Sum IL-2 preferentially bound to CD8+ T cells, especially activated CD8+ T cells, while IL-2 showed biased binding to Treg cells. As a result, 99mTc-sum IL-2 could detect tumor-infiltrating T cells. In the MC38 tumor model, SPECT/CT imaging showed the increased tumor uptake of 99mTc-sum IL-2 after αPD-L1 treatment, suggesting that the treatment significantly increased tumor-infiltrating T cells, resulting in a correspondingly significant curative effect. In addition, 99mTc-sum IL-2 SPECT/CT could also track the infiltration of antigen-specific cytotoxic CD8+ T cells during ACT therapy. CONCLUSION: 99mTc-sum IL-2 has great clinical potential for non-invasive and specific SPECT/CT imaging of tumor-infiltrating T cells as well as for timely prediction and evaluation of the therapeutic efficacy of ICB and ACT therapy.

Nanomodified Switch Induced Precise and Moderate Activation of CAR-T Cells for Solid Tumors.

Chimeric antigen receptor (CAR)-T cell therapy is a transformative treatment against advanced malignancies. Unfortunately, once administrated in vivo, CAR-T cells become out of artificial control, and fierce response to CAR-T therapy may cause severe adverse events, represented by cytokine-release syndrome and on-target/off-tumor effects. Here, a nanomodified switch strategy is developed, leading to sustained and precise "on-tumor only" activation of CAR-T cells. Here, original gelatinase-responsive nanoparticles (NPs) are used to selectively deliver the heterodimerizing switch, which is the key component of switchable CAR with separated activation modules. The "NanoSwitch" is tumor-specific, thus inactivated switchable CAR-T cells do little harm to normal cells, even if the normal cells express the target of CAR-T. Owing to the sustained-release effect of NPs, the CAR-T cells are activated smoothly, avoiding sudden release of cytokine. These data introduce NanoSwitch as a universal and applicable solution to safety problems of CAR-T therapy regardless of the target.

IL-2 delivery by engineered mesenchymal stem cells re-invigorates CD8+ T cells to overcome immunotherapy resistance in cancer.

Immune checkpoint blockade (ICB)-based immunotherapy depends on functional tumour-infiltrating lymphocytes (TILs), but essential cytokines are less understood. Here we uncover an essential role of endogenous IL-2 for ICB responsiveness and the correlation between insufficient IL-2 signalling and T-cell exhaustion as tumours progress. To determine if exogenous IL-2 in the tumour microenvironment can overcome ICB resistance, we engineered mesenchymal stem cells (MSCs) to successfully deliver IL-2 mutein dimer (SIL2-EMSC) to TILs. While MSCs have been used to suppress inflammation, SIL2-EMSCs elicit anti-tumour immunity and overcome ICB resistance without toxicity. Mechanistically, SIL2-EMSCs activate and expand pre-existing CD8+ TILs, sufficient for tumour control and induction of systemic anti-tumour effects. Furthermore, engineered MSCs create synergy of innate and adaptive immunity. The therapeutic benefits of SIL2-EMSCs were also observed in humanized mouse models. Overall, engineered MSCs rejuvenate CD8+ TILs and thus potentiate ICB and chemotherapy.

Lactate increases stemness of CD8 + T cells to augment anti-tumor immunity.

Lactate is a key metabolite produced from glycolytic metabolism of glucose molecules, yet it also serves as a primary carbon fuel source for many cell types. In the tumor-immune microenvironment, effect of lactate on cancer and immune cells can be highly complex and hard to decipher, which is further confounded by acidic protons, a co-product of glycolysis. Here we show that lactate is able to increase stemness of CD8+ T cells and augments anti-tumor immunity. Subcutaneous administration of sodium lactate but not glucose to mice bearing transplanted MC38 tumors results in CD8+ T cell-dependent tumor growth inhibition. Single cell transcriptomics analysis reveals increased proportion of stem-like TCF-1-expressing CD8+ T cells among intra-tumoral CD3+ cells, a phenotype validated by in vitro lactate treatment of T cells. Mechanistically, lactate inhibits histone deacetylase activity, which results in increased acetylation at H3K27 of the Tcf7 super enhancer locus, leading to increased Tcf7 gene expression. CD8+ T cells in vitro pre-treated with lactate efficiently inhibit tumor growth upon adoptive transfer to tumor-bearing mice. Our results provide evidence for an intrinsic role of lactate in anti-tumor immunity independent of the pH-dependent effect of lactic acid, and might advance cancer immune therapy.

In situ antigen modification-based target-redirected universal chimeric antigen receptor T (TRUE CAR-T) cell therapy in solid tumors.

BACKGROUND: Chimeric antigen receptor (CAR)-T cell therapy has demonstrated remarkable success in the treatment of hematologic malignancies, while the success has not yet been replicated in solid tumors. To some extent, the disappointing results can be attributed to the paucity and heterogeneity of target antigens in solid tumors since adequate antigens are the cornerstone for CAR-T cells to recognize and attack tumor cells. METHODS: We established a target-redirected universal CAR-T (TRUE CAR-T) cell therapeutic modality, in which exogenous antigens are loaded onto fusogenic nanoparticles to achieve in situ modification of cell membrane in solid tumors, providing targets for subsequent CAR-T cell therapy. The modification effect was evaluated by flow cytometry and confocal microscopic imaging. The in vivo metabolism and biodistribution of fusogenic antigen loaded nanoparticles (F-AgNPs) was explored using near infrared living imaging. Then F-AgNPs mediated in situ antigen modification were cooperated with corresponding CAR-T cell therapy, and its antitumor efficacy was evaluated using immune function experiments and further investigated in different tumor models. RESULTS: Using F-AgNPs, exogenous antigens were selectively modified onto tumor cell membranes through membrane fusion, spread deeper into tumor tissues through intercellular lipid transfer, further activating corresponding CAR-T cells and mediating antitumor immune responses towards multiple types of tumor cells, despite of their inherent antigen profiles. The cooperative treatment of F-AgNPs and CAR-T cell therapy successfully suppressed tumor proliferation and prolonged survival in both subcutaneous and peritoneally disseminated tumor models. CONCLUSION: The fusogenic nanoparticle-based in situ antigen modification overcome the limitation of target antigens paucity and heterogeneity in solid tumors, improving the efficacy and broadening the applications of CAR-T cells, thus establishing a novel TRUE CAR-T cell therapeutic modality with universal application and translational potential in immunotherapies for solid tumors.

Selective delivery of low-affinity IL-2 to PD-1+ T cells rejuvenates antitumor immunity with reduced toxicity.

PD-1 signaling on T cells is the major pathway that limits T cell immunity, but the efficacy of anti-PD-1 therapy has been limited to a small proportion of patients with advanced cancers. We fortuitously observed that anti-PD-1 therapy depends on IL-2 signaling, which raises the possibility that a lack of IL-2 limits anti-PD-1-induced effector T cell expansion. To selectively deliver IL-2 to PD-1+CD8+ tumor-infiltrating lymphocytes (TILs), we engineered a low-affinity IL-2 paired with anti-PD-1 (PD-1-laIL-2), which reduced affinity to peripheral Treg cells but enhanced avidity to PD-1+CD8+ TILs. PD-1-laIL-2 exerted better tumor control and lower toxicity than single or mixed treatments. Mechanistically, PD-1-laIL-2 could effectively expand dysfunctional and tumor-specific CD8+ T cells. Furthermore, we discovered that presumably dysfunctional PD-1+TIM3+ TILs are the dominant tumor-specific T cells responding to PD-1-laIL-2. Collectively, these results highlight that PD-1-laIL-2 can target and reactivate tumor-specific TILs for tumor regression as a unique strategy with stronger efficacy and lower toxicity.

Rejuvenation of tumour-specific T cells through bispecific antibodies targeting PD-L1 on dendritic cells.

Bispecific T-cell engagers (BiTEs) preferentially targeting tumour-associated antigens and stimulating CD3-mediated signalling are being used in patients to treat acute B-cell lymphoblastic leukemia. However, the potency of BiTEs in solid tumours is limited by their short half-life and their severe toxicity at relevant therapeutic doses. Here we report the design and in vivo performance of a bispecific antibody that simultaneously targets the murine T-cell co-receptor CD3ε and the murine immune checkpoint programmed-death ligand 1 (PD-L1). In multiple syngeneic tumour models, the bispecific antibody generated higher antitumour immune responses than conventional BiTEs targeting tumour-associated antigens and CD3ε. We found that the durable antigen-specific T-cell responses resulted from the rejuvenation of CD8 T cells, owing to the blockade of PD-L1 on dendritic cells (but not on tumour cells) and co-stimulation by B7-1&2 (a peripheral membrane protein on dendritic cells). Bispecific T-cell engagers targeting dendritic cells rather than tumour cells may represent a general means of T-cell rejuvenation for durable cancer immunotherapy.

A cytokine receptor-masked IL2 prodrug selectively activates tumor-infiltrating lymphocytes for potent antitumor therapy.

As a potent lymphocyte activator, interleukin-2 (IL-2) is an FDA-approved treatment for multiple metastatic cancers. However, its clinical use is limited by short half-life, low potency, and severe in vivo toxicity. Current IL-2 engineering strategies exhibit evidence of peripheral cytotoxicity. Here, we address these issues by engineering an IL-2 prodrug (ProIL2). We mask the activity of a CD8 T cell-preferential IL-2 mutein/Fc fusion protein with IL2 receptor beta linked to a tumor-associated protease substrate. ProIL2 restores activity after cleavage by tumor-associated enzymes, and preferentially activates inside tumors, where it expands antigen-specific CD8 T cells. This significantly reduces IL-2 toxicity and mortality without compromising antitumor efficacy. ProIL2 also overcomes resistance of cancers to immune checkpoint blockade. Lastly, neoadjuvant ProIL2 treatment can eliminate metastatic cancer through an abscopal effect. Taken together, our approach presents an effective tumor targeting therapy with reduced toxicity.

Tumor-Targeted Inhibition of Monocarboxylate Transporter 1 Improves T-Cell Immunotherapy of Solid Tumors.

Export of lactic acid from glycolytic cancer cells to the extracellular tumor milieu has been reported to enhance tumor growth and suppress antitumor immunity. In this study, a pH-activatable nanodrug is reported for tumor-targeted inhibition of monocarboxylate transporter-1 (MCT1) that reverses lactic acid-induced tumor immunosuppression. The nanodrug is composed of an MCT1 inhibitor (AZD3965) loaded inside the ultra-pH-sensitive nanoparticles (AZD-UPS NPs). AZD-UPS NP is produced by a microfluidics method with improved drug loading efficiency and optimal nanoparticle size over sonication methods. The nanodrug remains as intact micelles at pH 7.4 but rapidly disassembles and releases payload upon exposure to acidic pH. When combined with anti-PD-1 therapy, AZD-UPS NP leads to potent tumor growth inhibition and increases survival in two tumor models over oral administration of AZD3965 at dramatically reduced dose (>200-fold). Safety evaluations demonstrate reduced drug distribution in heart and liver tissues with decrease in toxic biomarkers such as cardiac troponin by the nanodrug. Increased T-cell infiltration and reduced exhaustive PD1+ Tim3+ T cells are found in tumors. These data illustrate that tumor-targeted inhibition of MCT1 can reverse the immune suppressive microenvironment of solid tumors for increased safety and antitumor efficacy of cancer immunotherapy.

Polycarbonate-based ultra-pH sensitive nanoparticles improve therapeutic window.

Stimuli-sensitive nanomaterials with cooperative response are capable of converting subtle and gradual biological variations into robust outputs to improve the precision of diagnostic or therapeutic outcomes. In this study, we report the design, synthesis and characterization of a series of degradable ultra-pH sensitive (dUPS) polymers that amplify small acidic pH changes to efficacious therapeutic outputs. A hydrolytically active polycarbonate backbone is used to construct the polymer with pH-dependent degradation kinetics. One dUPS polymer, PSC7A, can achieve activation of the stimulator of interferon genes and antigen delivery upon endosomal pH activation, leading to T cell-mediated antitumor immunity. While a non-degradable UPS polymer induces granulomatous inflammation that persists over months at the injection site, degradable PSC7A primes a transient acute inflammatory response followed by polymer degradation and complete tissue healing. The improved therapeutic window of the dUPS polymers opens up opportunities in pH-targeted drug and protein therapy.

Targeting tumors with IL-21 reshapes the tumor microenvironment by proliferating PD-1intTim-3-CD8+ T cells.

The lack of sufficient functional tumor-infiltrating lymphocytes in the tumor microenvironment (TME) is one of the primary indications for the poor prognosis of patients with cancer. In this study, we developed an Erbitux-based IL-21 tumor-targeting fusion protein (Erb-IL21) to prolong the half-life and improve the antitumor efficacy of IL-21. Compared with Erb-IL2, Erb-IL21 demonstrated much lower toxicity in vivo. Mechanistically, Erb-IL21 selectively expanded functional cytotoxic T lymphocytes but not dysfunctional CD8+ T cells in the TME. We observed that the IL-21-mediated antitumor effect largely depended on the existing intratumoral CD8+ T cells, instead of newly migrated CD8+ T cells. Furthermore, Erb-IL21 overcame checkpoint blockade resistance in mice with advanced tumors. Our study reveals that Erb-IL21 can target IL-21 to tumors and maximize the antitumor potential of checkpoint blockade by expending a subset of tumor antigen-specific CD8+ T cells to achieve effective tumor control.

Author Correction: A next-generation tumor-targeting IL-2 preferentially promotes tumor-infiltrating CD8+ T-cell response and effective tumor control.

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

Enhanced and Prolonged Antitumor Effect of Salinomycin-Loaded Gelatinase-Responsive Nanoparticles via Targeted Drug Delivery and Inhibition of Cervical Cancer Stem Cells.

BACKGROUND: Cervical cancer stem cells (CCSCs) represent a subpopulation of tumor cells that possess self-renewal capacity and numerous intrinsic mechanisms of resistance to conventional chemotherapy and radiotherapy. These cells play a crucial role in relapse and metastasis of cervical cancer. Therefore, eradication of CCSCs is the primary objective in cervical cancer therapy. Salinomycin (Sal) is an agent used for the elimination of cancer stem cells (CSCs); however, the occurrence of several side effects hinders its application. Nanoscale drug-delivery systems offer great promise for the diagnosis and treatment of tumors. These systems can be used to reduce the side effects of Sal and improve clinical benefit. METHODS: Sal-loaded polyethylene glycol-peptide-polycaprolactone nanoparticles (Sal NPs) were fabricated under mild and non-toxic conditions. The real-time biodistribution of Sal NPs was investigated through non-invasive near-infrared fluorescent imaging. The efficacy of tumor growth inhibition by Sal NPs was evaluated using tumor xenografts in nude mice. Flow cytometry, immunohistochemistry, and Western blotting were used to detect the apoptosis of CSCs after treatment with Sal NPs. Immunohistochemistry and Western blotting were used to examine epithelial-mesenchymal transition (epithelial interstitial transformation) signal-related molecules. RESULTS: Sal NPs exhibited antitumor efficacy against cervical cancers by inducing apoptosis of CCSCs and inhibiting the epithelial-mesenchymal transition pathway. Besides, tumor pieces resected from Sal NP-treated mice showed decreased reseeding ability and growth speed, further demonstrating the significant inhibitory ability of Sal NPs against CSCs. Moreover, owing to targeted delivery based on the gelatinase-responsive strategy, Sal NPs was more effective and tolerable than free Sal. CONCLUSION: To the best of our knowledge, this is the first study to show that CCSC-targeted Sal NPs provide a potential approach to selectively target and efficiently eradicate CCSCs. This renders them a promising strategy to improve the therapeutic effect against cervical cancer.

Hepatic Arterial Infusion Oxaliplatin Plus Oral S-1 Chemotherapy in Gastric Cancer with Unresectable Liver Metastases: A Case Series and Literature Review.

OBJECTIVE: The use of hepatic artery infusion (HAI) as a regional therapy against liver metastasis has rarely been reported in gastric cancer. This study aimed to evaluate the efficacy and safety of HAI oxaliplatin plus oral S-1 chemotherapy in first-line palliative therapy for gastric cancer with multiple liver metastases (GCLM). METHODS: We reviewed the records of five patients with GCLM who received HAI oxaliplatin (70-80 mg/m2 2 hrs d1,15) administered via a port-catheter system and S-1 with oral (35-40 mg/m2 twice daily for d1-14, 28 days for one cycle). Follow-up examination and efficacy evaluation were executed periodically. RESULTS: Until the 4th cycle response evaluation, the local effective rate and control rate were 40% and 80%, respectively; only one patient developed progression. HAI chemotherapy had a better local control against liver metastases (median progression-free survival: hepatic, 8.8 months vs. extrahepatic, 6.2 months), accompanied by less systemic toxicity, decreased tumour markers and symptomatic relief. CONCLUSION: HAI oxaliplatin plus oral S-1 chemotherapy can be considered as a new choice of first-line treatment for GCLM, which is also a good approach for controlling extrahepatic lesions with less adverse events.

A next-generation tumor-targeting IL-2 preferentially promotes tumor-infiltrating CD8+ T-cell response and effective tumor control.

While IL-2 can potently activate both NK and T cells, its short in vivo half-life, severe toxicity, and propensity to amplify Treg cells are major barriers that prevent IL-2 from being widely used for cancer therapy. In this study, we construct a recombinant IL-2 immunocytokine comprising a tumor-targeting antibody (Ab) and a super mutant IL-2 (sumIL-2) with decreased CD25 binding and increased CD122 binding. The Ab-sumIL2 significantly enhances antitumor activity through tumor targeting and specific binding to cytotoxic T lymphocytes (CTLs). We also observe that pre-existing CTLs within the tumor are sufficient and essential for sumIL-2 therapy. This next-generation IL-2 can also overcome targeted therapy-associated resistance. In addition, preoperative sumIL-2 treatment extends survival much longer than standard adjuvant therapy. Finally, Ab-sumIL2 overcomes resistance to immune checkpoint blockade through concurrent immunotherapies. Therefore, this next-generation IL-2 reduces toxicity while increasing TILs that potentiate combined cancer therapies.