The most effective methods for integrating gene therapy and genome editing to develop advanced cell therapy products remain unclear. The authors identify key technical processes in human T-cell manipulation and present an optimized toolkit for multiplex engineering.

The authors show that SDC1-mediated TLR2/TLR4 stimulation triggers intracellular osteopontin in mast cells to promote TNFα release, which hampers lethal neuroendocrine prostate cancer. The results open new opportunities for mast cell-based immunotherapy in prostate cancer.

A comprehensive understanding of the role of IL17 in pancreatic cancer is lacking. The authors show pancreatic epithelial IL17RA-mediated reprogramming of the immune pancreatic landscape, partially through regulation of B7-H4 expression, promotes the early stages of pancreatic tumorigenesis.

How ER stress promotes HCC progression is unclear. The authors show that it induces HCC release of SNHG6-carrying sEVs, which potentiate the immunosuppressive TME. SNHG6 knockdown improves anti-PD1 efficacy, suggesting a way to reverse the immunosuppressive TME.

The authors demonstrate that the anti–PD-1 nivolumab can reach and modify the GBM tumor microenvironment within 7 days of administration. Upregulation of compensatory immune checkpoint inhibition molecules may counter the benefits of nivolumab-induced intratumoral immune activation.

Analysis of paired baseline and on-treatment samples from patients with advanced pancreatic cancer enrolled in a clinical trial of anti-IL1β, anti-PD1, and chemotherapy shows systemic changes in monocytes that are not translated to intratumoral changes in myeloid populations.

CD70-specific CAR T cells are being developed for solid and liquid malignancies. The authors show that carcinoma in situ interactions between the CAR and endogenous CD70 push these cells toward exhaustion; knocking out CD70 prevents exhaustion and increases CAR T-cell functionality.

The authors show that iron supplementation reactivates antitumor T-cell responses and improves anti-PD1 efficacy in mice. Preliminary analysis of plasma ferritin levels in patients with cancer treated with anti-PD1, suggests iron may also modulate anti-PD1 responses in humans.

Resistance to anti–PD-1 remains a challenge clinically. The authors show a relationship between MerTK and DC metabolic reprogramming, contributing to an immunosuppressive tumor microenvironment and that reversing MerTK-dependent DC tolerizing dysfunction could help overcome anti-PD-1 resistance.

The authors show that PLXNB1 inhibition in the TME reprograms immune cells and vessels in TNBC models hampering tumor growth and metastasis, and enhancing the response to immunotherapy. Thus, PLXNB1 represents a promising therapeutic target for metastatic TNBC.