Macrophages hold promise as indicators of disease progression and therapeutic targets. Using a single-cell multi-omic approach, the authors uncover the heterogeneity of macrophages in human colorectal liver metastasis and identify distinct populations with opposite clinical relevance.

The authors show that intratumoral CD8⁺ T-cell exhaustion is regulated by IL18R signaling. IL18R-induced T-cell exhaustion is regulated by IL2/STAT5 and AKT/mTOR pathways and triggered by NLRP3 in the tumor microenvironment, suggesting IL18R as a new immunotherapy target.

Immunotherapy has had little success in PDAC. The authors report an in-depth investigation of the PDAC tumor microenvironment that highlights PD-1 and TIGIT, or their corresponding ligands, as potential targets for combinatorial therapy to treat this devastating disease.

After finding response rates of patients treated with neoadjuvant immunotherapy correlate with increased presence of cDC1, the authors perform a high-throughput screen that identifies 145 compounds that enhance tumor antigen cross-presentation, and further characterize the IAP antagonist AZD5582.

The authors show targeting DCs via the CD40 and type 1 IFN pathways generates systemic antitumor T-cell immunity in mouse models and NSCLC patients, highlighting a potential strategy for use alone or combined with T-cell targeting checkpoint inhibitors.

STAT6 inhibition using an antisense oligonucleotide inhibits M2 macrophage polarization and enhances antitumor effects of combination hypofractionated radiotherapy/anti–PD-1 in lung cancer, leading to abscopal effects and reduction of metastasis. Data highlight an alternative therapeutic approach for treatment-resistant tumors.

The authors show that tumor cell–derived microparticles loaded with methotrexate can activate neutrophils, attenuating expression of PD-1 by lysosome degradation, which promotes T-cell antitumor responses. The data suggest a potential combination therapy for use with anti–PD-L1.

Compared to CAR T cells containing CD28 or 4-1BB costimulatory domains, HVEM-based CAR T cells exhibit reduced exhaustion and have superior proliferation and effector function. Treatment with these cells yields improved therapeutic activity in several solid tumor models.

The authors show in lung-cancer models that acute influenza virus infection has a long-term effect on the tumor microenvironment impacting antitumor immune responses, tumor progression and survival, with implications for prophylactic and therapeutic management of lung cancer patients.

A role for autoantibodies reactive to cardiac antigens is identified as a key mechanism behind cardiac-related toxicity associated with concurrent radiotherapy and immune checkpoint blockade. The data highlight B cells as potential targets to mitigate cardiotoxicity.