Targeting antibody-inaccessible immune resistance with small-molecule immunotherapy

Area of Science:

• Oncology
• Immunology
• Pharmacology

Background:

• Immune checkpoint inhibitors (ICIs) have transformed cancer therapy but benefit only a subset of patients.
• Tumor immune evasion often involves intracellular, metabolic, and epigenetic pathways resistant to antibody-based ICIs.
• There is a critical need for novel immunotherapeutic strategies beyond cell-surface checkpoint inhibition.

Purpose of the Study:

• To provide an integrated overview of small-molecule immunotherapies.
• To examine the challenges and future directions in overcoming cancer immune resistance.
• To highlight the potential of small molecules in combination with ICIs.

Main Methods:

• Review of recent advancements in small-molecule immunotherapies.
• Analysis of strategies targeting intracellular immune suppression pathways.
• Examination of clinical translation challenges and successes.

Main Results:

• Small-molecule immunotherapies can infiltrate tumors and target intracellular compartments.
• These agents modulate metabolic, epigenetic, and myeloid-intrinsic pathways involved in immune suppression.
• Small molecules show potential to reprogram the tumor microenvironment and enhance ICI responsiveness.

Conclusions:

• Small-molecule immunotherapies are mechanistically complementary to antibody-based ICIs.
• Rational combination strategies are essential for targeting both surface and intracellular resistance mechanisms.
• Careful consideration of dosing, delivery, and patient selection is crucial for clinical translation.