STING Reactivation in Melanoma Cells for Stronger TIL Response

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Solution Overview

Problem

Existing cancer therapies utilizing STING activation in antigen presenting cells are limited, and there is a lack of understanding regarding its activation in tumor cells, particularly in subjects with deficient STING expression, which hampers effective antitumor T cell responses.

Innovation Solution

Administering a demethylating agent to demethylate STING proteins in tumor cells, followed by a STING agonist, to enhance STING expression and antigenicity, and administering HLA-matched tumor infiltrating lymphocytes (TILs) to enhance T cell responses.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If STING agonists are administered to activate STING signaling in antigen presenting cells, then antitumor T cell responses are enhanced, but the therapy is ineffective in subjects with deficient STING expression in tumor cells

Engineering Contradiction:

Improveefficacy of STING activation therapyVSAvoidapplicability to subjects with deficient STING expression

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent applies preliminary action by using demethylating agents to restore STING expression in tumor cells before administering STING agonists. This preparatory step ensures that the tumor cells have functional STING proteins available to respond to subsequent agonist treatment, thereby resolving the contradiction between enhancing antitumor responses and addressing deficient STING expression.

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The patent changes the epigenetic state (methylation status) of the STING gene in tumor cells through demethylating agents. This parameter change restores STING expression from a deficient state to a functional state, enabling the tumor cells to respond to STING agonists and improving the reliability of the therapy in previously refractory subjects.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If demethylating agents are used to restore STING expression in tumor cells, then STING agonist therapy becomes effective, but the treatment complexity increases

Engineering Contradiction:

ImproveSTING signaling activation in tumor cellsVSAvoidtreatment protocol complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent merges two therapeutic approaches into a single integrated protocol: demethylating agents that restore STING expression and STING agonists that activate the restored pathway. This combination is administered in a coordinated manner, where the demethylating agent prepares the tumor cells and the STING agonist activates the recovered signaling pathway, simplifying the overall treatment approach while maintaining effectiveness.

Inventive Principle:

Principle #5Merging (Combining)

3Quantity of substance

If TIL expansion is performed ex vivo, then antitumor T cell responses are enhanced, but the trafficking of TILs into tumors is insufficient without adequate chemokine signals

Engineering Contradiction:

Improvenumber of TILsVSAvoidTIL trafficking into tumor sites

Core Design Contradiction:

Quantity of substanceVSEase of operation

Solution Approach 1:

The patent uses CXCR3-binding chemokines (such as CXCL9 and CXCL10) as intermediary signaling molecules. These chemokines are induced in tumor cells through STING activation and serve as mediators that guide the trafficking of expanded TILs from the bloodstream into the tumor microenvironment, thereby resolving the contradiction between having sufficient TILs and ensuring their effective delivery to tumor sites.

Inventive Principle:

Principle #24Intermediary (Mediator)

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

Enhances T cell responses by increasing CXCR3-binding chemokines, recruiting T cells into tumors, improving immune checkpoint therapy efficacy, and enhancing TIL trafficking and function.

Implementation Method 1

administering to the subject a composition comprising a demethylating agent in an amount effective to demethylate STING proteins in the tumor cells

Methodology Applied

Scientific EffectDNA demethylation:

Implementation Method 2

administering to the subject a therapeutically effective amount of a STING agonist

Methodology Applied

Scientific EffectSTING activation:

Implementation Method 3

STING is an endoplasmic reticulum-resident signaling molecule. It is responsible for controlling the transcription of several host defense genes

Methodology Applied

Scientific EffectSignal transduction:

Implementation Method 4

Downstream induction of CXCR3-binding chemokines such as CXCL10 and CXCL9 in melanoma cell lines following their stimulation with the STING agonist

Methodology Applied

Scientific EffectChemotaxis:

Data Source

PatentUS12599621B2Enhancing anti-tumor response in melanoma cells with defective sting signaling

Publication Date: 2026.04.14 H LEE MOFFITT CANCER CENTER & RESEARCH INSTITUTE INC

AI summary

Disclosed herein is a method for enhancing antitumor T cell responses in subjects. The method involves administering to the subject in need thereof a composition comprising a demethylating agent in an amount effective to demethylate STING proteins in the tumor cells. This method is particularly useful in subjects with deficient STING expression in the tumor cells. Therefore, also disclosed is a method for treating a tumor in a subject that involves detecting in a biopsy sample from the subject reduced STING expression, reduced cGAS expression, or a combination thereof; and then administering to the subject a demethylating agent in an amount effective to demethylate STING proteins in the tumor cells. The method can further involve administering to the subject a therapeutically effective amount of a STING agonist. The method can further involve administering to the subject tumor infiltrating lymphocytes (TILs), such as HLA-matched TILs.