Clinical landscape of macrophage-reprogramming cancer immunotherapies

Abstract

Tumour-associated macrophages (TAMs) sustain a tumour-supporting and immunosuppressive milieu and therefore aggravate cancer prognosis. To modify TAM behaviour and unlock their anti-tumoural potential, novel TAM-reprogramming immunotherapies are being developed at an accelerating rate. At the same time, scientific discoveries have highlighted more sophisticated TAM phenotypes with complex biological functions and contradictory prognostic associations. To understand the evolving clinical landscape, we reviewed current and past clinically evaluated TAM-reprogramming cancer therapeutics and summarised almost 200 TAM-reprogramming agents investigated in more than 700 clinical trials. Observable overall trends include a high frequency of overlapping strategies against the same therapeutic targets, development of more complex strategies to improve previously ineffective approaches and reliance on combinatory strategies for efficacy. However, strong anti-tumour efficacy is uncommon, which encourages re-directing efforts on identifying biomarkers for eligible patient populations and comparing similar treatments earlier. Future endeavours will benefit from considering the shortcomings of past treatment strategies and accommodating the emerging complexity of TAM biology.

Fig. 1. Timeline of clinically evaluated macrophage-reprogramming therapeutics.

a Number of macrophage-reprogramming therapeutics entering clinical trials each year since 2000, coloured by target group. b A timeline showing when each macrophage-reprogramming therapeutic target was first clinically investigated in cancer. Bubble colours indicate macrophage target groups.

Fig. 2. Clinical landscape of macrophage-reprogramming therapeutics in cancer.

a Number of therapeutic agents that have been investigated in clinical trials. Therapeutics are shown by target group and coloured by clinical development phase as of January 2024. b Number of treated patients by target group, coloured by the development status. c Number of therapeutic agents by target group, coloured by development status and highest clinical development phase at the time of discontinuation. Percentages indicate proportions of discontinued therapeutics. d Bar plots of macrophage-reprogramming therapeutics with ongoing clinical development as of January 2024, grouped by molecule type and coloured by clinical development phase.

Fig. 3. TAM-reprogramming treatment targets by combinatory treatment regimen and subcellular localisation.

a Dot plot showing how commonly macrophage-reprogramming therapeutics have been investigated in combination with other treatment types. Dot size indicates number and dot colour proportion of macrophage-reprogramming therapeutics investigated with the indicated treatment combinations, separately for each target. ‘Monotherapy phase 1’ indicates therapeutics at phase 1 clinical development not yet investigated in combination with other treatments. Percentages were calculated from all TAM-reprogramming therapeutics (n = 194). b Illustration depicting subcellular localisation of macrophage-reprogramming therapeutic targets. Targets are coloured by clinical development status with coloured areas depicting proportions among therapeutics against the same target.