Identifying different ways to stimulate the anti-tumor immune response is essential to enrich the immunotherapy arsenal with more and improved treatment options for patients.

Despite the fact that immuno-oncology has become one of the leading areas in cancer research in recent years, the arsenal of such treatments that clinicians have at their disposal remains limited, hampered by the high biological complexity of the tumor and immune ecosystems that poses barriers to the clinical translation of seemingly promising preclinical findings and the use of approved therapies for more tumor types and broader populations of patients. During the past decade, huge effort has been made to elucidate the interplay of the immune system and different cancer types and deepen the understanding of immunobiology to discover new immunotherapeutic targets and sole or combination treatment approaches. Three papers in this issue of Nature Cancer present different ways in which the immune system could be stimulated against cancer.

Lerner et al. focused on understanding the CD8+ T cell response to tumors that have downregulated their expression of major histocompatibility complex (MHC) class I and thus are generally thought to be capable of evading the immune system. Using glioma and melanoma models, they demonstrated that although loss of MHC class I expression blocks tumor-cell killing by CD8+ T cells in cell cultures, as expected, this was not the case in the context of immune checkpoint blockade therapy directed against tumors growing in mice. The authors found that the observed cytotoxic activity required earlier CD8+ T cell priming by macrophages or other antigen-presenting cells, and the subsequent expression on T cells of NKG2D, a receptor more frequently associated with the innate immune response and whose cytotoxic effects were triggered once bound to NKG2DL, its cognate ligand on tumor cells. This provocative study highlights a CD8+ T cell–mediated mechanism through which MHC class I–negative cancer cells can still be targeted in a tumor-antigen-agnostic manner that bridges adaptive immunity through activation of T cell receptors with the cytotoxic effects of innate immune signaling pathways. The authors of this study and the accompanying News & Views article by Christopher Rudd discuss the implications of this work and topics for further research, including on the precise cytotoxic mechanisms triggered and how they could be employed with therapeutic specificity across tumor types.

Mei et al. set out to understand how immune cell populations affect immunotherapy efficacy in glioblastoma, a notoriously hard-to-treat tumor type that is generally poorly responsive to immunotherapy. Using single-cell and spatial transcriptomics of glioblastoma samples obtained from patients at first diagnosis, after neoadjuvant combination immune and targeted therapy, or at tumor recurrence, they identified a subpopulation of tumor-associated macrophages that showed enrichment in patients with poor response to immunotherapy. These monocyte-derived macrophages were functionally plastic and were marked by expression of SIGLEC9, which the authors showed in mouse experiments acted as an immune checkpoint molecule that helped induce an immunosuppressive environment. Conversely, they showed that deletion of this molecule in mice promoted an immune-permissive macrophage and T cell microenvironment and synergized with classic immune checkpoint blockade of PD-1 and PD-L1 to reduce glioblastoma growth. In their News & Views article, Marron and Guerriero provide a thoughtful discussion of how these findings further efforts to map and target the immune brain tumor microenvironment, and outline some of the questions that should be addressed in future work.

Wu et al. sought to understand how the known opposing roles of IL-2 in cancer — immunosuppressive through stimulation of the high-affinity trimeric receptor IL-2Rαβγ on regulatory T cells versus immune-activating through the intermediate-affinity dimeric receptor IL-2Rβγ on effector T cells and natural killer cells — can be exploited, given the severe toxicity reported for anti-cancer IL-2 therapy. Studying wild-type IL-2 and versions biased to binding to the trimeric or dimeric receptor, they found that in contrast to existing efforts to develop IL-2Rβγ-biased approaches that limit the IL-2Rα-mediated impact on regulatory T cells, the effects of IL-2Rα on tumor-specific CD8+ T cells were essential for improved efficacy of immune checkpoint blockade in a number of solid tumor cell line models in vivo. They further engineered an IL-2Rα-biased agonist — a mutant version of IL-2 with reduced affinity for IL-2Rβγ — and found that this IL-2 analog effectively activated tumor-specific CD8+ T cells and preserved the ability to synergize with anti-PD1 therapy for tumor control in mice while also limiting toxicity to some extent. As discussed by the authors in the manuscript and accompanying Research Briefing, despite the limitations of their preclinical efforts, these findings uncover an additional layer of the complex IL-2 biology that could aid in the development of better and safer therapies.

Although much work remains to be conducted to translate these preclinical findings to the clinic, the three studies presented in this issue highlight the wealth of knowledge to be gained by immunobiology discovery science en route to identifying those aspects of the immune tumor environment that would be most amenable to therapeutic targeting.