Immune checkpoint inhibitors have limited efficacy against hepatocellular carcinoma. The authors show that combining anti-CXCR4 with standard anti–PD-1 therapy enhances anticancer efficacy and improves survival in murine hepatocellular carcinoma models. The benefit is mediated by reprogramming of intratumoral Batf3+ cDC1s.

The function of tumor-reactive CD4⁺ T cells is unclear. The authors identify tumor-infiltrating neoantigen-specific CD4⁺ T cells in endometrial cancer. The cells have cytotoxic function and express CXCL13, GZMB, and CCL5, suggesting a role in tumor immune surveillance.

HITOC improves pleural mesothelioma prognosis; however, the mechanism remains unclear. In a mesothelioma mouse model, the authors demonstrate that HITOC improves cancer control through immune landscape remodeling and can be further enhanced by dual immune checkpoint inhibition therapy.

Not all patients with HER2-positive esophagogastric adenocarcinoma benefit from chemoimmunotherapy. The authors show that patients with high systemic inflammation particularly benefit from inclusion of chemotherapy, whereas others strongly benefit from dual immunotherapy alone, providing a new insight for treatment selection.

The authors demonstrate the feasibility of using 3D microfluidic cultures of patient-derived organotypic tumor spheroids to evaluate factors influencing the efficacy of solid tumor–directed chimeric antigen receptor (CAR) T-cell therapy and identify combination strategies to overcome CAR T-cell resistance.

Mechanisms of resistance to immune checkpoint inhibitor therapies remain unclear. The authors reveal the functional significance of tumor-infiltrating T cells in resistant tumors, which instruct immunosuppressive inflammation in mouse and human cancers responsive to IL1 and TNFα.

Setdb1 suppresses tumor immunogenicity by repressing the expression of immunogenic genomic elements that can serve as tumor antigens and trigger an intracellular interferon loop. This work demonstrates how targeting epigenetic factors can activate immunogenic tumor factors for therapeutic benefits.

NK cells exhibit antitumor properties in the prostate cancer tumor microenvironment. The authors report the development of a tri-specific engager that facilitates NK cell engagement with prostate cancer cells, in combination with enhanced cytokine signaling, to enhance tumor control.

The authors show that HSP90 inhibition by pimitespib reduces the number and immunosuppressive function of FOXP3^high regulatory T cells, resulting in activation of tumor-specific CD8⁺ T cells and overcoming PD-1 blockade resistance. The data suggest pimitespib as a regulatory T cell–targeted immunotherapy.

This study demonstrates that nucleus accumbens–associated protein 1 (NAC1), which is overexpressed in ovarian cancer, results in the recruitment CXCR6⁺ myeloid-derived suppressor cells to the tumor and diminishes CD8⁺ T-cell function. NAC1 inhibition improves anti–PD-1 therapy in ovarian cancer.