To address this, a multifunctional nanoparticle, TPI@RPB, was constructed with RGD-PEG-BSA as the carrier for tumor-targeted delivery, while co-loading the self-synthesized endoplasmic reticulum (ER) target photosensitizer TSE-Ppa and Indoleamine 2,3-dioxygenase 1 (IDO-1) inhibitor 1-MT...In vivo, TPI@RPB not only demonstrates active tumor targeting but also significant antitumor efficacy with a favorable safety profile; specifically, tumor weight reduced to 13.70%, intratumoral CD8+ T-cell infiltration increased 1.92-fold, Treg cells decreased to 51.7%, and splenic effector-memory T cells increased 4.70-fold of control, with no observable systemic toxicity. These results suggest that ER-targeted PDT combined with IDO-1 blockade effectively remodels the tumor microenvironment and elicits durable antitumor immunity in TNBC.

Additionally, LOX-catalyzed lactate oxidation can generate abundant H2O2 to promote the release of NLG919 from the polyprodrug nanoreactors, thus reprogramming the immunosuppressive TME via cooperative lactate depletion and NLG919-mediated indoleamine 2,3-dioxygenase 1 inhibition in tumors. As a result, the intelligent polyprodrug nanoreactors can elicit intense antitumor immunity after intravenous administration, especially in combination with PD-L1 checkpoint blockade, thereby realizing effective and long-lasting suppression of primary and metastatic tumors without the concern of systemic toxicity.

Importantly, the accumulation of myeloid-derived suppressor cells (MDSCs), a key driver of tumor progression and metastasis, decreased in the primary tumor, metastatic liver, and lung of mice treated with indoximod and melatonin combination. Our findings revealed that melatonin enhances the immunotherapeutic efficacy of indoximod in TNBC.

Here, we design and construct an in situ injectable therapeutic hydrogel encapsulating 1-methyl-d-tryptophan (1-d-MT), a small-molecule competitive inhibitor of indoleamine 2,3-dioxygenase, and meloxicam, a selective inhibitor of cyclooxygenase-2 (Ge1MT/Mel hydrogel) to prevent postoperative tumor metastasis and relapse. Importantly, the Ge1MT/Mel hydrogel markedly stimulates a potent antitumor immune response in the cancer lesion microenvironment, increasing antitumor immune cells including CD8+ T cells, as well as elevating antitumor cytokines such as interferon-γ. Overall, combination immunotherapy via the Ge1MT/Mel hydrogel after surgery represents a promising strategy to minimize residual tumor burden and reduce recurrence risk following tumor resection.

IO102-IO103 plus pembrolizumab prolonged progression-free survival compared with pembrolizumab alone in patients with advanced melanoma in the first-line setting; however, statistical significance was missed for the primary endpoint. The combination was well tolerated with no added significant systemic toxicity. These data show the potential benefit of this combination in untreated advanced melanoma.

P2, N=63, Completed, IO Biotech | Active, not recruiting --> Completed | Trial completion date: Nov 2024 --> Feb 2026 | Trial primary completion date: Jan 2024 --> Nov 2025

Herein, by using a one-pot approach, we developed a carrier-free nanoreshaper (QN NP) through coordinating manganese ions (Mn2+) with quercetin (Qc) and the indoleamine 2,3-dioxygenase 1 inhibitor NLG919 to lift these restrictions...Furthermore, combining QN NPs with an anti-PD-L1 antibody generated robust synergistic activity, leading to cooperative suppression of both primary tumor growth and pulmonary metastases. This carrier-free nanoreshaping strategy overcomes the dual challenges of stromal fibrosis and immune evasion, providing a promising paradigm for developing combined immunotherapies based on physical barrier disruption and microenvironment reprogramming.

This effect was suppressed after 1-methyltryptophan (1-MT) treatment, indicating that it is IDO-dependent...Experimental evidence has revealed that mouse CD4+ T cells undergo apoptosis via IDO following T. spiralis infection, and that weakened proliferation leads to an imbalance in mouse immune function, facilitating the smooth survival of T. spiralis and evasion of host immune attack. These findings provide new directions and insights for studying the immune escape mechanism of T. spiralis and for the prevention and treatment of T. spiralis infection.

P2, N=30, Recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | N=15 --> 30

In addition, the immunosuppressive microenvironment exacerbated by postoperative hypoxia is degraded via the cooperation of NLG919, which blocks the IDO-1 signaling pathway and CaCO3, which consumes lactic acid. Based on these improvements, well-designed MOFs effectively inhibit bilateral tumor growth/metastasis and offer a successful paradigm for improving the overall prognosis of HIFU.