Flipping the Immune Switch: Small-Molecule and Biologic Pharmacology to Convert the Immunosuppressive Tumor Microenvironment into an Immunoreactive One

The tumor microenvironment (TME) is one of the most formidable barriers to durable cancer immunotherapy. Far from being a passive bystander, the TME actively suppresses anti-tumor immunity through a coordinated interplay of immunosuppressive cell populations — tumor-associated macrophages, myeloid-derived suppressor cells, regulatory T cells — alongside dysregulated kinase signaling, epigenetic silencing of immunogenic programs, aberrant developmental pathway activation, and engagement of immune checkpoint networks that extend well beyond the established PD-1/CTLA-4 axis. Pharmacologically converting this immunosuppressive landscape into one permissive to immune activation remains one of the most critical and underexplored challenges in contemporary immuno-oncology.

This Research Topic focuses on the pharmacological strategies, molecular targets, and translational frameworks that drive the directional conversion from immunosuppression to immune activation within solid tumors. Contributions are welcome on small-molecule and biologic agents that reprogram myeloid populations; novel immune checkpoint targets and their pharmacological modulation; epigenetic and kinase-directed drugs that reactivate silenced immunogenic programs; the role of Wnt/β-catenin and other developmental signaling networks in immune exclusion; regulated cell death modalities used as triggers of immunogenic activation; and rational combination regimens that synergise pharmacological TME remodeling with established immunotherapies.

Distinct from collections focused on TME disruption broadly, on nanotechnology-based delivery, or on resistance reversal alone, this Topic is anchored on pharmacological agents — small molecules and biologics — that flip the directionality of the immune response within the TME. Mechanism-of-action diversity is welcome, but contributions must address how the proposed intervention converts immunosuppression into productive anti-tumor immunity, not merely modulate the TME or reduce resistance.

We welcome Original Research, Review, Brief Research Report, Case Report, Clinical Trial, Data Report, FAIR² Data, General Commentary, Hypothesis and Theory, Methods, Mini Review, Opinion, Perspective, Systematic Review, Technology and Code. This Research Topic focuses on the following topics, but not limited to:

1. Myeloid cell reprogramming — pharmacological conversion of tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) from pro-tumorigenic to anti-tumor phenotypes.

2. Novel immune checkpoint targets beyond PD-1/CTLA-4 — pharmacological modulation of LGALS1, CD47, TIGIT, VISTA, and emerging checkpoints active in the immunosuppressive TME.

3. Wnt/β-catenin and developmental signaling in immune exclusion — small-molecule and biologic disruption of tumor-intrinsic pathways that physically restrict immune infiltration.

4. Kinase signaling networks in TME immunosuppression — targeting TAM- and MDSC-associated kinase pathways to shift the immune balance toward activation.

5. Epigenetic agents as immune-priming pharmacology — HDAC, DNMT, and BET-bromodomain inhibitors used to reactivate silenced immunogenic programs in the TME (not as standalone epigenetic anti-cancer agents).

6. Regulated cell death as a pharmacological trigger of immunogenic remodeling — ferroptosis, pyroptosis, and necroptosis induction used specifically to convert “cold” TMEs into “hot” ones (not as standalone cell-death biology).

7. Switch-oriented combination strategies — rational pairing of TME-reprogramming pharmacology with checkpoint blockade, adoptive cell therapy, or other established immunotherapies.

8. Translational and clinical perspectives — biomarkers of the suppression-to-activation switch, patient stratification, and early-phase clinical evidence for TME-reprogramming agents.